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Prevalence of BRCA mutations and founder effect in high-risk Hispanic families.

UNLABELLED: Approximately 12% of the U.S. population is Hispanic, with the majority residing in urban centers such as Los Angeles. The prevalence of BRCA mutations among high-risk Hispanic families is unknown. METHODS: One hundred and ten unrelated probands of Hispanic origin, with a personal or family history of breast and/or ovarian cancer, presented for genetic cancer risk assessment, were enrolled in an Institutional Review Board-approved registry and underwent BRCA testing. Haplotype analyses were done if BRCA mutations were observed in two or more unrelated probands. RESULTS: Mean age at diagnosis was 37 years (range = 23-59) for the 89 (81%) probands with invasive breast cancer. Overall, 34 (30.9%) had deleterious mutations (25 in BRCA1, 9 in BRCA2), 25 (22.7%) had one or more unclassified variants, and 51 (46.4%) had negative results. The mean pretest mutation probability using the Couch model, Myriad model, and BRCAPro was 19.6% (range = 4-77%). The combined average mutation probability was 32.8% for carriers, 15.5% for noncarriers, and 12.9% for variant carriers (P < 0.0001). The most common deleterious mutation was 185delAG (4 of 34, 11.8%). The Hispanic 185delAG carrier families share the same haplotype from D17s1320 through BRCA1, as do two reference Ashkenazi Jewish families. Haplotype analyses of additional recurrent BRCA1 mutations [IVS5+1G>A (n=2),S955X (n = 3), R1443X (n = 3), and 2552delC (n = 2)] also suggest founder effects, with four of six mutations seen almost exclusively in families with Latin American/Caribbean or Spanish ancestry. CONCLUSION: This is the largest study to date of high-risk Hispanic families in the United States. Six recurrent mutations accounted for 47% (16 of 34) of the deleterious mutations in this cohort. The BRCA1185delAG mutation was prevalent (3.6%) in this clinic-based cohort of predominantly Mexican descent, and shared the Ashkenazi Jewish founder haplotype.

Adult↗

Breast and ovarian cancer in relatives of cancer patients, with and without BRCA mutations.

BACKGROUND: First-degree relatives of patients with breast or ovarian cancer have increased risks for these cancers. Little is known about how their risks vary with the patient's cancer site, carrier status for predisposing genetic mutations, or age at cancer diagnosis. METHODS: We evaluated breast and ovarian cancer incidence in 2,935 female first-degree relatives of non-Hispanic White female patients with incident invasive cancers of the breast (n = 669) or ovary (n = 339) who were recruited from a population-based cancer registry in northern California. Breast cancer patients were tested for BRCA1 and BRCA2 mutations. Ovarian cancer patients were tested for BRCA1 mutations. We estimated standardized incidence ratios (SIR) and 95% confidence intervals (95% CI) for breast and ovarian cancer among the relatives according to the patient's mutation status, cancer site, and age at cancer diagnosis. RESULTS: In families of patients who were negative or untested for BRCA1 or BRCA2 mutations, risks were elevated only for the patient's cancer site. The breast cancer SIR was 1.5 (95% CI, 1.2-1.8) for relatives of breast cancer patients, compared with 1.1 (95% CI, 0.8-1.6) for relatives of ovarian cancer patients (P = 0.12 for difference by patient's cancer site). The ovarian cancer SIR was 0.9 (95% CI, 0.5-1.4) for relatives of breast cancer patients, compared with 1.9 (95% CI, 1.0-4.0) for relatives of ovarian cancer patients (P = 0.04 for difference by site). In families of BRCA1-positive patients, relatives' risks also correlated with the patient's cancer site. The breast cancer SIR was 10.6 (95% CI, 5.2-21.6) for relatives of breast cancer patients, compared with 3.3 (95% CI, 1.4-7.3) for relatives of ovarian cancer patients (two-sided P = 0.02 for difference by site). The ovarian cancer SIR was 7.9 (95% CI, 1.2-53.0) for relatives of breast cancer patients, compared with 11.3 (3.6-35.9) for relatives of ovarian cancer patients (two-sided P = 0.37 for difference by site). Relatives' risks were independent of patients' ages at diagnosis, with one exception: In families ascertained through a breast cancer patient without BRCA mutations, breast cancer risks were higher if the patient had been diagnosed before age 40 years. CONCLUSION: In families of patients with and without BRCA1 mutations, breast and ovarian cancer risks correlate with the patient's cancer site. Moreover, in families of breast cancer patients without BRCA mutations, breast cancer risk depends on the patient's age at diagnosis. These patterns support the presence of genes that modify risk specific to cancer site, in both carriers and noncarriers of BRCA1 and BRCA2 mutations.

Adult↗

Early detection of breast and ovarian cancer in families with BRCA mutations.

Women at risk of breast and ovarian cancer due to a genetic predisposition may opt for preventive surgery or surveillance. The aim of this study was to determine the effectiveness of surveillance in families with a BRCA mutation. Sixty-eight BRCA-families underwent surveillance using annual mammography, transvaginal ultrasound, and estimation of CA125. Two hundred and two women had at least one breast examination, and 138 at least one examination of the ovaries. After a mean follow-up of 33 months, breast cancer was detected in 21 women, four with lymph node metastases. After a mean follow-up of 37 months, six advanced ovarian cancers were detected. The percentage of metastatic breast cancers in the current study appeared to be acceptable. However, because these women have a high-risk of developing breast cancer, they still have a substantial risk of developing metastatic disease under surveillance. Surveillance for ovarian cancer was not effective.

Adult↗

Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: systematic evidence review for the U.S. Preventive Services Task Force.

BACKGROUND: Clinically significant mutations of BRCA1 and BRCA2 genes are associated with increased susceptibility for breast and ovarian cancer. Although these mutations are uncommon, public interest in testing for them is growing. PURPOSE: To determine benefits and harms of screening for inherited breast and ovarian cancer susceptibility in the general population of women without cancer presenting for primary health care in the United States. DATA SOURCES: MEDLINE (1966 to 1 October 2004), Cochrane Library databases, reference lists, reviews, Web sites, and experts. STUDY SELECTION: Eligibility was determined by inclusion criteria specific to key questions about risk assessment, genetic counseling, mutation testing, prevention interventions, and potential adverse effects. DATA EXTRACTION: After review of studies, data were extracted, entered into evidence tables, and summarized by using descriptive or statistical methods. Study quality was rated by using predefined criteria. DATA SYNTHESIS: Tools assessing risks for mutations and referral guidelines have been developed; their accuracy, effectiveness, and adverse effects in primary care settings are unknown. Risk assessment, genetic counseling, and mutation testing did not cause adverse psychological outcomes, and counseling improved distress and risk perception in the highly selected populations studied. Intensive cancer screening studies are inconclusive. Chemoprevention trials indicate risk reduction for breast cancer in women with varying levels of risk, as well as increased adverse effects. Observational studies of prophylactic surgeries report reduced risks for breast and ovarian cancer in mutation carriers. LIMITATIONS: No data describe the range of risk associated with BRCA mutations, genetic heterogeneity, and moderating factors; studies conducted in highly selected populations contain biases; and information on adverse effects is incomplete. CONCLUSIONS: A primary care approach to screening for inherited breast and ovarian cancer susceptibility has not been evaluated, and evidence is lacking to determine benefits and harms for the general population.

Breast Neoplasms↗

Histopathology, FIGO stage, and BRCA mutation status of ovarian cancers from the Gilda Radner Familial Ovarian Cancer Registry.

Studies of the histopathology of ovarian cancer arising in patients with germline mutations in BRCA1 or BRCA2 have shown inconsistent findings. We analyzed the large number of tumors from women enrolled in the Gilda Radner Familial Ovarian Cancer Registry for correlations between histopathology and BRCA mutation status. Histopathology slides and reports were reviewed for histology, grade, and stage for cancers of the ovary or peritoneum in 220 women from 126 Gilda Radner Familial Ovarian Cancer Registry families. At least one affected member of each family was analyzed for mutations in the BRCA1 and BRCA2 genes, and tumors from mutation-positive families were compared with those from mutation-negative families. Of 70 patients from 38 BRCA1-positive families, 69 had epithelial ovarian carcinoma and one had a dysgerminoma. Fifteen of 16 patients from nine BRCA2-positive families had epithelial ovarian cancer, and one had a primary peritoneal cancer. Of 134 patients from 79 BRCA-negative families, 118 had epithelial ovarian carcinoma, 11 had ovarian borderline tumors, three had nonepithelial tumors, and two had primary peritoneal carcinoma. There were fewer grade 1 (p < 0.001) and stage I (p = 0.005) cancers in patients from BRCA-positive families than in patients from BRCA-negative families. Neither mucinous nor borderline tumors were found in the BRCA-positive families. In conclusion, ovarian cancers arising in women from BRCA-positive families are more likely to be high-grade and have extraovarian spread than tumors arising in women from BRCA-negative families. Borderline and mucinous tumors do not appear to be part of the phenotype of families with germline mutations in the BRCA genes.

Female↗

Ductal carcinoma in situ in BRCA mutation carriers.

PURPOSE: The current literature suggests that ductal carcinoma in situ (DCIS) of the breast is infrequently diagnosed in patients with BRCA germline mutations. We studied women at high risk of hereditary breast cancer syndromes who underwent testing for BRCA1 and BRCA2 to estimate DCIS prevalence and incidence in known BRCA-positive women compared with high-risk women who were mutation negative. METHODS: We analyzed breast event outcomes in a retrospective cohort of 129 BRCA-positive and 269 BRCA-negative women undergoing genetic testing for a BRCA mutation between September 1996 and December 2003 at University of California, San Francisco. We estimated the frequency of DCIS and invasive cancer and time to breast events from birth using a Cox proportional hazard model for competing risks. Histologic grade of DCIS was also compared between groups. RESULTS: Among BRCA carriers, 48 (37%) had DCIS (with or without invasive cancer) compared with 92 noncarriers (34%). Univariate analysis showed that both DCIS and invasive cancer had an earlier onset in mutation carriers than in noncarriers, although on a per-woman basis, this difference was not statistically significant. High-grade DCIS was more common in BRCA1 mutation carriers than in patients without a mutation (P = .02). CONCLUSION: DCIS is equally as prevalent in patients who carry deleterious BRCA mutations as in high familial-risk women who are noncarriers, but occurs at an earlier age. Our results argue for the consideration of DCIS as a criterion for BRCA risk assessments with appropriate weighting in prediction models such as BRCAPRO.

Adult↗

Epidemiology of breast cancer among BRCA mutation carriers: an overview.

Mutations in BRCA1 and BRCA2 have been associated with an increased lifetime risk of breast and ovarian cancers. Many of the well-recognized risk factors and risk modifiers in other women appear to operate similarly in BRCA mutation carriers. However, current evidence suggests that BRCA-related breast cancer risk is positively associated with pregnancy and parity, while smoking may reduce the risk. The incidence of BRCA1-related breast cancer is high before the age of 35 years and oral contraceptive use for 5 or more years is associated with increased risk of this disease among women carrying BRCA1 mutations.

Adult↗

Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: recommendation statement.

This statement summarizes the U.S. Preventive Services Task Force (USPSTF) recommendations on genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility, along with the supporting scientific evidence. The complete information on which this statement is based, including evidence tables and references, is included in the evidence synthesis available through the USPSTF Web site (http://www.preventiveservices.ahrq.gov). The recommendation is also posted on the Web site of the National Guideline Clearinghouse (http://www.guideline.gov).

Breast Neoplasms↗

Outcome of preventive surgery and screening for breast and ovarian cancer in BRCA mutation carriers.

PURPOSE: To prospectively determine the impact of genetic counseling and testing on risk-reduction strategies and cancer incidence in a cohort of individuals at hereditary risk for breast and ovarian cancer. PATIENTS AND METHODS: Two hundred fifty-one individuals with BRCA mutations were identified at a single comprehensive cancer center from May 1, 1995, through October 31, 2000. Uniform recommendations regarding screening and preventive surgery were provided in the context of genetic counseling. Patients were followed for a mean of 24.8 months (range, 1.6 to 66.0 months) using standardized questionnaires, chart reviews, and contact with primary physicians. RESULTS: Frequency of cancer surveillance by physical examinations and imaging studies increased after genetic counseling and testing. Twenty-one breast, ovarian, primary peritoneal, or fallopian tube cancers were detected after receipt of genetic test results. Among 29 individuals choosing risk-reducing mastectomy after testing, two were found to have occult intraductal breast cancers. Among 90 individuals who underwent risk-reducing salpingo-oophorectomy, one early-stage ovarian neoplasm and one early-stage fallopian tube neoplasm were found. Radiographic or tumor marker-based screening detected six breast cancers, five of which were stage 0/I, one early-stage primary peritoneal cancer, and three stage I or II ovarian cancers. Six additional breast cancers were detected by physical examination between radiographic screening intervals; four of these six tumors were stage I. No stage III or stage IV malignancies were detected after genetic testing. CONCLUSION: This study provides prospective evidence that genetic counseling and testing increased surveillance and led to risk-reducing operations, which resulted in diagnosis of early-stage tumors in patients with BRCA1 and BRCA2 mutations.

Adult↗

Prophylactic bilateral salpingo-oophorectomy compared with surveillance in women with BRCA mutations.

OBJECTIVE: The objective of this study was to evaluate clinical factors associated with choosing prophylactic bilateral salpingo-oophorectomy (BSO) over surveillance in women with a BRCA1 or BRCA2 mutation. METHODS: Between 1996 and 2005, 139 women who tested positive for a BRCA1 or BRCA2 mutation were identified. Thirty-three women were excluded due to a personal history of ovarian or fallopian tube cancer before genetic testing, resulting in 106 women for the final analysis. The characteristics of women who underwent prophylactic BSO were compared with those choosing surveillance. RESULTS: Sixty-five of the BRCA mutation carriers (61%) underwent prophylactic BSO. Median age at BSO was 45.6 years. Median time from disclosure of genetic test results to surgery was 4.6 months. Eighty-five percent of women who underwent prophylactic BSO were parous compared with 66% of women who chose surveillance (P = .03). A previous diagnosis of breast cancer was noted in 72% of women who underwent prophylactic BSO compared with 46% of women undergoing surveillance (P < .01). Fifty-two women (80%) had hysterectomy performed at the time of BSO. Two women had incidental ovarian cancer diagnosed at time of surgery. CONCLUSION: Age greater than 40 years, parity, and a personal history of breast cancer were associated with choosing prophylactic BSO in our cohort. A short time interval was noted from the time of receiving positive genetic test results to undergoing prophylactic surgery.

Adult↗

Three primary malignancies related to BRCA mutation successively occurring in a BRCA1 185delAG mutation carrier.

The 185delAG and 5382insC mutations in the BRCA1 gene and the 6174delT mutation in the BRCA2 gene (the Ashkenazi mutations) have been found to be significantly more common among Jews of eastern European ancestry (1 in 40, 2.5%) in comparison to the general population (1 in 800 to 1 in 300, 0.12-0.33%). Carriers of these mutations, especially the BRCA1 185delAG mutation, have a significantly increased lifetime risk of breast and ovarian carcinoma and other carcinomas as compared to non-carriers. A case of three primary malignancies related to the BRCA1 185delAG mutation successively occurring in a carrier of this mutation, is described. The patient successively developed breast carcinoma, ovarian micropapillary serous carcinoma and peritoneal papillary serous carcinoma. Immunohistochemical staining results have indicated that these tumors are three separate primary malignancies. This case illustrates that ovarian serous borderline tumors (including micropapillary serous carcinoma) and peritoneal papillary serous carcinomas should be considered, like breast and ovarian carcinomas, tumors expressed in BRCA mutation carriers.

Antineoplastic Combined Chemotherapy Protocols↗

Smoking and the risk of breast cancer among carriers of BRCA mutations.

The effect of cigarette smoking on the risk of breast cancer is controversial, although most studies show little or no effect. It has been suggested that smoking may reduce the risk of developing hereditary breast cancer. We completed a case-control study on 1,097 women with breast cancer who were BRCA1 or BRCA2 mutation carriers and 1,097 age-matched controls with a mutation in the same gene but without breast cancer. There were no statistically significant differences between the cases and controls in terms of the number of current and ex-smokers (41.2% and 40.4%, respectively) or the age at smoking commencement (18.2 years and 18.5 years, respectively). There were no statistically significant differences between cases and controls regarding beginning smoking within 5 years of menarche (OR = 1.03; 95% CI 0.83 to l.28) or before the first pregnancy (OR = 1.09; 95% CI = 0.90 to 1.33). In conclusion, contrary to our previous report, smoking does not appear to be a risk factor for breast cancer among carriers of BRCA mutations.

Adolescent↗

Family issues in a psychoeducation group for women with a BRCA mutation.

Few services exist for women who test positive for BRCA1 and BRCA2 mutations despite the distress that they and their families may experience. We present one model of a time-limited family-oriented psychoeducation group to provide information and support for nine women who received positive test results. We report on five family-oriented themes that arose from the discussions: distress about possible transmission to children; family conflict about testing; concerns about disclosure; different coping styles and decision making; and underlying family conflict and unresolved grief. We also include recommendations from these women to enhance the services available to families by expanding assessment, and providing written literature and contact information. In addition, referrals for a psychoeducation group, community support group, or psychotherapy may be useful for individuals, couples and families who are considering genetic testing for BRCA mutations.

Adult↗

Analyses of p53 expression pattern and BRCA mutations in patients with double primary breast and ovarian cancer.

OBJECTIVE: To analyze the somatic pattern of p53 expression and BRCA germline mutation status in Israeli patients with both ovarian (OvCa) and breast cancer (BrCa). METHODS: The study group comprised 43 Israeli patients with OvCa, all of whom had previous primary BrCa. p53 immunohistochemistry (IHC) on all available archival tissues and genotyping for the three predominant Jewish germline BRCA1-2 mutations were carried out. Samples from 64 patients with solitary OvCa and 61 with solitary BrCa were similarly analyzed as controls. RESULTS: p53 expression pattern and the immunopositivity rate were similar in the ovarian and breast tumors within the study group and in the two control groups: positive p53 staining was detected in 68% of ovarian tumors in the study group compared with 71.9% in the controls, and in 19.4% of the BrCa tissues versus 21.3% in the controls. Within the study group, advanced stage OvCa had a higher rate of p53 expression (84%) compared to early stage disease (38.5%) (P = 0.006). This difference was not apparent in the solitary OvCa control group. OvCa in BRCA1-2 mutation carriers from the study group were more likely to display positive p53 staining (79%), especially in tumors diagnosed before the age of 60 (90%) compared with the OvCa of noncarriers (60%), but this difference was statistically insignificant. The p53 expression rate in BrCa samples from the study group was not associated with BRCA1-2 mutation status. CONCLUSIONS: Positive p53 expression, detected by IHC, in OvCa patients with previous primary BrCa is significantly higher in advanced stage disease in BRCA1-2 mutation carriers. There is a higher positive p53 expression somatically in OvCa in BRCA1-2 carriers in whom OvCa was diagnosed before the age of 60 years, although this trend is not statistically significant. These observations suggest that somatic p53 inactivation may be an important event in ovarian tumorigenesis in this subset of patients.

Aged↗

[Effect of Cancer Antigen-125 Elimination Rate Constant K and BRCA Mutation Status on the Prognosis of Interval Debulking Surgery in Advanced High-Grade Serous Ovarian Cancer].

OBJECTIVE: To investigate the predictive value of the cancer antigen-125 elimination rate constant K (KELIM) for treatment response and prognosis in patients with advanced high-grade serous ovarian cancer (HGSOC) undergoing neoadjuvant chemotherapy followed by interval debulking surgery (NACT-IDS), and to analyze the combined prognostic significance of KELIM and the mutation status of breast cancer susceptibility gene (BRCA). METHODS: A total of 106 patients with advanced HGSOC who had undergone NACT-IDS were retrospectively enrolled. The KELIM values during neoadjuvant chemotherapy were calculated, and patients were divided into high- and low-KELIM groups using a cutoff value of 1.0. Clinicopathological characteristics, R0 resection rates, and platinum sensitivity rates were compared between the two groups. Logistic regression analysis was performed to identify predictive factors for R0 resection, while Kaplan-Meier survival analysis and Cox proportional hazards regression were performed to evaluate factors associated with progression-free survival (PFS). Furthermore, the patients were stratified according to both KELIM and BRCA status to assess the risk of platinum-resistant recurrence in each subgroup. RESULTS: The R0 resection rate was higher in the KELIM &#x2265; 1 group than in the KELIM < 1 group (77.1% vs 55.2%), and the difference was statistically significant (P = 0.024). Multivariate logistic regression analysis showed that KELIM was an independent predictor of R0 resection (odds ratio [OR] = 2.922, 95% CI: 1.112-7.678). Survival analysis demonstrated longer PFS in the KELIM &#x2265;1 group compared with that in the KELIM <1 group (33.0 months vs 18.0 months), and the difference was statistically significant (P < 0.001). Multivariate Cox regression analysis showed that KELIM &#x2265; 1 was associated with a reduced risk of disease progression (hazard ratio [HR] = 0.481, 95% CI: 0.280-0.826). Combined stratification analysis revealed that no platinum-resistant recurrence was observed in the subgroup with both KELIM &#x2265;1 and a BRCA-positive status (0/21). Compared with patients with KELIM <1 and a BRCA-negative status, this subgroup exhibited a lower risk of platinum-resistant recurrence (OR = 0.053, 95% CI: 0.003-0.932, P = 0.006). CONCLUSION: KELIM is an effective dynamic biomarker for predicting surgical outcomes and PFS in patients undergoing NACT-IDS. Combined stratification by KELIM and BRCA status allows more precise identification of the patient population with both KELIM &#x2265;1 and BRCA-positive status, who have an extremely low risk of platinum-resistant recurrence, thereby providing an important basis for individualized treatment and risk stratification management in patients with advanced HGSOC.

Humans↗

Differentially androgen-modulated genes in ovarian epithelial cells from BRCA mutation carriers and control patients predict ovarian cancer survival and disease progression.

Epidemiological studies have implicated androgens in the etiology and progression of epithelial ovarian cancer. We previously reported that some androgen responses were dysregulated in malignant ovarian epithelial cells relative to control, non-malignant ovarian surface epithelial (OSE) cells. Moreover, dysregulated androgen responses were observed in OSE cells derived from patients with germline BRCA-1 or -2 mutations (OSEb), which account for the majority of familial ovarian cancer predisposition, and such altered responses may be involved in ovarian carcinogenesis or progression. In the present study, gene expression profiling using cDNA microarrays identified 17 genes differentially expressed in response to continuous androgen exposure in OSEb cells and ovarian cancer cells as compared to OSE cells derived from control patients. A subset of these differentially affected genes was selected and verified by quantitative real-time reverse transcription-polymerase chain reaction. Six of the gene products mapped to the OPHID protein-protein interaction database, and five were networked within two interacting partners. Basic leucine zipper transcription factor 2 (BACH2) and acetylcholinesterase (ACHE), which were upregulated by androgen in OSEb cells relative to OSE cells, were further investigated using an ovarian cancer tissue microarray from a separate set of 149 clinical samples. Both cytoplasmic ACHE and BACH2 immunostaining were significantly increased in ovarian cancer relative to benign cases. High levels of cytoplasmic ACHE staining correlated with decreased survival, whereas nuclear BACH2 staining correlated with decreased time to disease recurrence. The finding that products of genes differentially responsive to androgen in OSEb cells may predict survival and disease progression supports a role for altered androgen effects in ovarian cancer. In addition to BACH2 and ACHE, this study highlights a set of potentially functionally related genes for further investigation in ovarian cancer.

Acetylcholinesterase↗

Challenges in the early diagnosis and staging of Fallopian-tube carcinomas associated with BRCA mutations.

The histopathologic diagnosis of fallopian-tube carcinoma has been traditionally made at an advanced stage. More recently, predictive genetic BRCA testing is leading to the recognition in prophylactic oophorectomy specimens of clinically occult tubal carcinomas that are frequently in situ or small early-stage invasive carcinomas. These early lesions present a challenge in diagnosis and staging because the available criteria for the histopathologic diagnosis and staging of tubal carcinoma were derived from the clinicopathologic experience derived from the usual high-stage tubal carcinomas. The detection of early-stage tubal carcinomas requires that all tubal tissue be submitted for histologic examination. The diagnostic criteria for tubal in situ carcinoma have been defined, although the natural history of this lesion is unclear. Similarly defined criteria for a diagnosis of tubal dysplasia are lacking. Any early, invasive tubal carcinoma should be staged using a refined staging system suitable for early stage and fimbrial carcinomas. The adoption of these methods should increase our knowledge of early-stage tubal carcinoma and may add to our understanding of the development of ovarian-epithelial neoplasia.

Carcinoma↗