Screening for familial ovarian cancer: failure of current protocols to detect ovarian cancer at an early stage according to the international Federation of gynecology and obstetrics system.

PURPOSE: To assess the effectiveness of annual ovarian cancer screening (transvaginal ultrasound and serum CA-125 estimation) in detecting presymptomatic ovarian cancer in women at increased genetic risk. PATIENTS AND METHODS: A cohort of 1,110 women at increased risk of ovarian cancer were screened between January 1991 and March 2004; 553 were moderate-risk individuals (4% to 10% lifetime risk) and 557 were high-risk individuals (> 10% lifetime risk). Outcome measurements include the number and stage of screen-detected cancers, the number and stage of cancers not detected at screening, the number of equivocal screening results requiring recall/repetition, and the number of women undergoing surgery for benign disease. RESULTS: Thirteen epithelial ovarian malignancies (12 invasive and one borderline), developed in the cohort. Ten tumors were detected at screening: three International Federation of Gynecology and Obstetrics (FIGO) stage I (including borderline), two stage II, four stage III, and one stage IV. Of the three cancers not detected by screening, two were stage III and one was stage IV; 29 women underwent diagnostic surgery but were found not to have ovarian cancer. CONCLUSION: Annual surveillance by transvaginal ultrasound scanning and serum CA-125 measurement in women at increased familial risk of ovarian cancer is ineffective in detecting tumors at a sufficiently early stage to influence prognosis. With a positive predictive value of 17% and a sensitivity of less than 50%, the performance of ultrasound does not satisfy the WHO screening standards. In addition, the combined protocol has a particularly high false-positive rate in premenopausal women, leading to unnecessary surgical intervention.     

Surveillance of women at high risk for hereditary ovarian cancer is inefficient

To determine the effectiveness of annual gynaecological screening (pelvic examination, transvaginal ultrasound, and CA-125), a prospective cohort study of women at high risk for hereditary ovarian cancer was conducted. Women were offered DNA analysis followed by either annual screening or prophylactic bilateral salpingo-oophorectomy (BSO). Study population consisted of 512 high-risk women (median follow-up 2.07 years, range 0-9.4 years): 265 women (52%) had a BRCA mutation. Persisting abnormalities indicated diagnostic surgery in 24 women resulting in one primary ovarian cancer FIGO stage IIIc was found. The effectiveness of screening was studied by calculating the probability of finding ovarian cancers in the BRCA-1 and BRCA-2 carrier group and comparing this to the identified number of ovarian cancers. The number of ovarian cancer patients found at surveillance was in accordance with the predicted number of ovarian cancers. A total number of 169 women underwent prophylactic BSO: one ovarian cancer stage IIb was found. In conclusion, the surveillance programme for hereditary ovarian cancer does identify patients with ovarian cancer but is very inefficient considering the high number of surveillance visits and the advanced stage of ovarian cancer in the identified patient. For prevention of advanced stage ovarian cancer, prophylactic BSO from age 35-40 years is a more efficient alternative.     

Ovarian cancer screening with annual transvaginal sonography: findings of 25,000 women screened

BACKGROUND: Ovarian cancer has the highest mortality rate of all gynecologic malignancies, and most women present with advanced-stage disease. The current investigation was performed to determine the efficacy of annual transvaginal sonography (TVS) as a screening method for ovarian cancer. METHODS: Annual TVS screening was performed on 25,327 women from 1987 to 2005. Asymptomatic women aged>or=50 years and women aged>or=25 years who had a family history of ovarian cancer were eligible for participation in this trial. RESULTS: Among 364 patients (1.4%) with a persisting ovarian tumor on TVS who underwent exploratory laparoscopy or laparotomy with tumor removal, 35 primary invasive ovarian cancers, 9 serous ovarian tumors of low malignant potential, and 7 cancers metastatic to the ovary were detected. Stage distribution was as follows: 28 patients had stage I disease, 8 patients had stage II disease, and 8 patients had stage III disease. Four patients died of disease, 2 patients died of other causes, and 38 patients were alive and well from 0.5 years to 15.8 years after diagnosis (mean, 5.3 years). Nine women developed ovarian cancer within 12 months of a negative screen (false-negative results), and 3 of these patients died of disease. TVS screening had a sensitivity of 85.0%, specificity of 98.7%, positive predictive value of 14.01%, and negative predictive value of 99.9%. After 107,276 screening years, there have been 7 ovarian cancer deaths in the annually screened population and 3 ovarian cancer deaths among women who were noncompliant. Excluding patients with nonepithelial or borderline ovarian malignancies, the survival of patients with ovarian cancer in the annually screened population was 89.9%+/-10.1% at 2 years and 77.2%+/-22.8% at 5 years. CONCLUSIONS: TVS screening, when it was performed annually, was associated with a decrease in disease stage at detection and with case-specific ovarian cancer mortality, but it was not effective in detecting ovarian cancers in women who had normal ovarian volume.     

Molecular profiling of computed tomography screen-detected lung nodules shows multiple malignant features.

RATIONALE AND PURPOSE: Low-dose spiral computerized axial tomography (spiral CT) is effective for the detection of small early lung cancers. Although published data seem promising, there has been a significant degree of discussion concerning the potential of overdiagnosis in the context of spiral CT-based screening. The objective of the current study was to analyze the phenotypic and genetic alterations in the small pulmonary malignancies resected after detection in the University of Navarra/International Early Lung Cancer Action Project spiral CT screening trial and to determine whether their malignant molecular features are similar to those of resected lung tumors diagnosed conventionally. EXPERIMENTAL DESIGN: We analyzed 17 biomarkers of lung epithelial malignancy in a series of 11 tumors resected at our institution during the last 4 years (1,004 high-risk individuals screened), using immunohistochemistry and fluorescence in situ hybridization (FISH). A parallel series of 11 gender-, stage-, and histology-matched lung cancers diagnosed by other means except screening was used as control. RESULTS: The molecular alterations and the frequency of phenotypic or genetic aberrations were very similar when screen-detected and nonscreen-detected lung cancers were compared. Furthermore, most of the alterations found in the screen-detected cancers from this study were concordant with what has been described previously for stage I-II lung cancer. CONCLUSIONS: Small early-stage lung cancers resected after detection in a spiral CT-based screening trial reveal malignant molecular features similar to those found in conventionally diagnosed lung cancers, suggesting that the screen-detected cancers are not overdiagnosed.     

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.     

Effectiveness of breast cancer surveillance in BRCA1/2 gene mutation carriers and women with high familial risk.

PURPOSE: Women with a high breast cancer risk due to a familial predisposition may choose between preventive surgery and regular surveillance. The effectiveness of surveillance in high-risk women and especially BRCA1/2 mutation carriers is unknown. We present first results from a single large family cancer clinic. PATIENTS AND METHODS: Women with breast cancer risk over 15% were examined by physical examination every 6 months and mammography every year. Detection rates and screening parameters were calculated for the total group and separately for different age and genetic risk groups. RESULTS: At least one examination was performed in 1,198 women: 449 moderate and 621 high-risk women and 128 BRCA1/2 mutation carriers. Within a median follow-up of 3 years, 35 breast cancers were detected (four ductal carcinoma-in-situ; 31 invasive tumors); the average detection rate was 9.7 per 1,000. Detection rates (95% confidence interval) for moderate and high-risk women and BRCA1/2 carriers were 3.3 (1.1 to 8.6), 8.4 (5.4 to 13.2), and 33 (17 to 63) per 1,000 person-years, respectively. The ratio of observed cases versus breast cancers expected in an average-risk population of comparable age was 2.7, 7.0 and 23.7 respectively. Overall, node negativity was 65%; 34% of primary tumors were less than 10 mm; sensitivity was 74%. Results with respect to tumor stage and sensitivity were less favorable in BRCA1/2 carriers and in women under the age of 40. CONCLUSION: It is possible to identify young women at high risk for breast cancer. The number of cancers detected was significantly greater than expected in an age-matched average-risk population and related to the risk category. Overall, screening parameters were comparable to population screening data, with less favorable results in the youngest age group (< 40) and BRCA1/2 carriers.     

Cigarette smoking and risk of epithelial ovarian cancer

Background An increased risk of mucinous ovarian tumors among cigarette smokers has been observed in multiple studies. The association of smoking with other histologic types of ovarian cancer is less clear, but potentially holds greater importance for prevention of disease incidence and mortality. Methods In a population-based study of 812 women with ovarian cancer diagnosed in western Washington State from 2002–2005 and 1,313 controls, we assessed the risk associated with cigarette smoking, with a particular focus on tumor subgroups jointly classified according to the degree of invasiveness and histology. Information was collected through in-person interviews, and logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Results The incidence of both borderline and invasive mucinous ovarian tumors was increased among women with a history of cigarette smoking (ORs and 95% CIs = 1.8, 1.2–2.9, and 1.8, 0.8–4.3, respectively). Increases in risk of these tumor types were most evident among women with greater smoking duration and pack-years of exposure, and among those who had smoked within the prior 15 years. We noted no clear patterns of risk of serous tumors with duration or pack-years of smoking; however, risk of these tumor types was somewhat elevated among women who had smoked within the previous 15 years (for borderline serous tumors, OR and 95% CI = 1.5, 0.9–2.3; for invasive serous tumors, OR and 95% CI = 1.4, 1.1–1.9). The risk of endometrioid, clear cell, and the remaining histologic types of invasive ovarian cancer was not increased among smokers. Conclusion In the aggregate, evidence is insufficient to determine whether smoking is linked with risk of serous or other non-mucinous histologic types of ovarian cancer. Studies that employ additional histopathologic and molecular techniques to more accurately delineate subsets of tumors may improve our understanding of the impact of smoking on ovarian cancer risk.     

Six families prone to ovarian cancer.

Six families are presented with multiple cases of ovarian cancer, mainly serous cystadenocarcinoma. Three families had concomitant aggregation of breast cancer, suggesting genetic determinants common to both tumors. The exceptional cancer risk in these families prompted prophylactic oophorectomy in 14 asymptomatic women from four families. Review of the original microscopic sections from 8 women revealed that 3, representing two families, had abnormalities of ovarian surface epithelium and mesothelial tissue, which may be of etiologic significance and portend neoplastic changes. To enable early detection and prevention of ovarian cancer, new diagnostic techniques and etiologic studies should be applied whenever possible to high-risk families.     

Self administered screening for hereditary cancers in conjunction with mammography and ultrasound

We evaluated the feasibility of an automated tablet computer application providing a family and personal history based cancer risk assessment for hereditary breast, ovarian, endometrial and colorectal cancers. 1,002 women presenting for screening mammography and 1,000 presenting for ultrasound were offered screening. The application calculated the risk of BRCA mutations using BRCAPRO, Myriad and Tyrer–Cuzick risk assessment models. Lifetime risk of breast and ovarian cancer was assessed with the BRCAPRO, Claus and Tyrer–Cuzick models. Colorectal and endometrial cancer risk was calculated via the MMRpro model. Patients were identified as high-risk based on thresholds 10 % or greater risk for carrying genetic mutations or 20 % or greater lifetime risk of breast or ovarian cancer. The percent of women found to be high-risk by a single risk assessment tool ranged from 0.5 to 5.3 %. Combining assessment tools found 9.3 % of women to be high-risk. The risk assessments performed similarly for the mammography and ultrasound cohorts with yields (combining assessment tools) of 9.2 and 9.4 % respectively. The average ages of all the high-risk women were 45.8 and 39.6 years for the mammography and ultrasound cohorts respectively. Difficulties encountered included a need for software upgrade, wireless network unreliability and hardware theft. Automated family history screening can identify women probably at high-risk for hereditary cancers efficiently. The number of women identified is increased by employing multiple risk assessment models simultaneously. Surveying women in conjunction with ultrasound identified women at increased risk as effectively and at a younger age than with screening mammography.     

Risk of specific types of ovarian cancer after borderline ovarian tumors in Denmark: A nationwide study

Population-based evidence regarding risk of ovarian cancer after a borderline ovarian tumor (BOT) is sparse. We aimed to examine the incidence of specific types of ovarian cancer in women with serous or mucinous BOTs in a nationwide cohort study with up to 36 years of follow-up. Using the nationwide Danish Pathology Data Bank, we identified 4,281 women with a BOT (2,058 serous BOTs and 2,223 mucinous BOTs) in Denmark during 1978–2012. We computed standardized incidence ratios (SIRs) to compare the incidence of ovarian cancer among women with BOTs compared to general population rates. We found that a serous BOT was especially and strongly associated with subsequent serous ovarian cancer (SIR = 9.2; 95% CI: 6.8–12.2), and that a mucinous BOT was strongly related to mucinous ovarian cancer (SIR = 18.6; 95% CI: 10.8–29.8). The SIRs remained elevated ≥10 years after a serous BOT and up to 5–9 years after a mucinous BOT. The increased incidence of serous ovarian cancer in women with a serous BOT was mostly pronounced in women <50 years at the serous BOT diagnosis. In conclusion, women with a serous BOT experience long-term increased incidence of serous ovarian cancer, and women with a mucinous BOT have long-term elevated incidence of mucinous ovarian cancer compared to the general population. This is the first population-based study to show compelling evidence of the histo-specific increased risk of ovarian cancer following specific types of BOTs. Thus, these results are supportive of the hypothesis that BOTs may be precursor lesions to carcinomas of the corresponding histologic type.     

Risk of nonovarian cancer in a nationwide-based study of nearly 5000 women with borderline ovarian tumors in Denmark

Evidence regarding cancer risk after borderline ovarian tumors (BOTs) is limited. We conducted a nationwide cohort study examining the incidence of nonovarian cancers in women with serous or mucinous BOTs compared with the general female population with up to 41 years of follow-up. Through the nationwide Pathology Registry, we identified nearly 5000 women with BOTs (2506 serous and 2493 mucinous) in Denmark, 1978 to 2018. We computed standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) as relative risk estimates of specific nonovarian cancers. Compared with general female population rates, women with serous BOTs had increased rates of particularly malignant melanoma (SIR = 1.9; 95% CI: 1.3-2.6), thyroid cancer (SIR = 3.0; 95% CI: 1.4-5.4) and myeloid leukemia (SIR = 3.2; 95% CI: 1.5-5.8), and women with mucinous BOTs had elevated rates of lung cancer (SIR = 1.7; 95% CI: 1.3-2.1), pancreatic cancer (SIR = 1.9; 95% CI: 1.2-2.9) and myeloid leukemia (SIR = 2.3; 95% CI: 0.9-4.7). We found no convincing association with neither breast nor colorectal cancer in women with BOTs. This is the first large nationwide study showing that women with specific types of BOTs have increased risks of several nonovarian cancers, likely due to some shared risk factors or genetic characteristics.     

No efficacy of annual gynaecological screening in BRCA1/2 mutation carriers; an observational follow-up study

BRCA1/2 mutation carriers are offered gynaecological screening with the intention to reduce mortality by detecting ovarian cancer at an early stage. We examined compliance and efficacy of gynaecological screening in BRCA1/2 mutation carriers. In this multicentre, observational, follow-up study we examined medical record data of a consecutive series of 888 BRCA1/2 mutation carriers who started annual screening with transvaginal ultrasonography and serum CA125 between 1993 and 2005. The women were annually screened for 75% of their total period of follow-up. Compliance decreased with longer follow-up. Five of the 10 incident cancers were interval tumours, diagnosed in women with a normal screening result within 3-10 months before diagnosis. No difference in stage distribution between incident screen-detected and interval tumours was found. Eight of the 10 incident cancers were stage III/IV (80%). Cancers diagnosed in unscreened family members had a similar stage distribution (77% in stage III/IV). The observed number of cases detected during screening was not significantly higher than expected (Standardized Incidence Ratio (SIR): 1.5, 95% confidence interval: 0.7-2.8). For the subgroup that was fully compliant to annual screening, a similar SIR was found (1.6, 95% confidence interval: 0.5-3.6). Despite annual gynaecological screening, a high proportion of ovarian cancers in BRCA1/2 carriers are interval cancers and the large majority of all cancers are diagnosed in advanced stages. Therefore, it is unlikely that annual screening will reduce mortality from ovarian cancer in BRCA1/2 mutation carriers.     

Population based study of coffee, alcohol and tobacco use and risk of ovarian cancer

Coffee, alcohol and tobacco use have been examined in many epidemiologic studies of ovarian cancer but findings have generally been inconclusive. To explain prior inconsistent findings, we sought to determine whether associations with these exposures might vary by histologic subtype of ovarian cancer or menopausal status at diagnosis. We conducted a population-based case-control study in eastern Massachusetts and New Hampshire involving 549 women with newly-diagnosed epithelial ovarian cancer and 516 control women selected either by random digit dialing or through lists of residents. Coffee and alcohol consumption was assessed through a semi-quantitative food-frequency questionnaire, and information on tobacco smoking was collected through personal interview. Consumption of coffee and caffeine was associated with increased risk for ovarian cancer but only among premenopausal women. There was no increase in risk for ovarian cancer overall associated with tobacco or alcohol use in either pre- or post-menopausal women. Association of borderline significance for tobacco and invasive serous cancers and alcohol and mucinous cancers were observed but reduced after adjustment for coffee consumption. We conclude that coffee and caffeine consumption may increase risk for ovarian cancer among premenopausal women and are findings that have some epidemiologic and biologic support.     

Methylation profiles of sporadic ovarian tumors and nonmalignant ovaries from high-risk women.

PURPOSE: The purpose of this research was to examine the DNA methylation profiles of primary sporadic ovarian cancers and ovarian tissues from high-risk women. EXPERIMENTAL DESIGN: We analyzed the DNA methylation status of nine cancer-related genes in 49 primary ovarian tumors, 39 nonmalignant ovarian tissues obtained from 16 women with no known risk and from 23 high-risk women with a strong family history of breast and/or ovarian cancer or BRCA1 germ-line mutations, and 11 ovarian cancer cell lines, by methylation-specific PCR. RESULTS: Our findings are as follows: (a) methylation rates of four of nine genes, RASSF1A (41%), HIC1 (35%), E-cadherin (29%), and APC (18%) were significantly higher in tumors compared with controls. At least one of the four genes was methylated in 76% of the tumors; (b) a low frequency of methylation was present in nonmalignant tissues; (c) no significant differences in methylation frequencies were seen between the nonmalignant ovarian tissues from women at high-risk and those with no known risk of developing ovarian cancer; (d) methylation of the BRCA1 gene was found in 10% of sporadic tumors but in none of the samples from women with a germ-line BRCA1 mutation; and (e) ovarian cancer cell lines showed a similar frequency of methylation to ovarian tumors except for the HIC1 gene. CONCLUSIONS: Our results suggest that aberrant methylation of specific genes, including two not described previously, may be important in ovarian cancer pathogenesis but not in ovaries at risk for cancer development.     

Gene expression profiles of serous, endometrioid, and clear cell subtypes of ovarian and endometrial cancer.

PURPOSE: The presence of similar histologic subtypes of epithelial ovarian and endometrial cancers has long been noted, although the relevance of this finding to pathogenesis and clinical management is unclear. Despite similar clinical characteristics, histologic subtypes of cancers of the ovary and endometrium are treated according to organ of origin. This study compares the gene expression profiles of analogous histologic subtypes of cancers of the ovary and endometrium using the same genomic platform to determine the similarities and differences between these tumors. EXPERIMENTAL DESIGN: Gene expression profiles of 75 cancers (endometrioid, serous, and clear cell) of the ovary and endometrium, five renal clear cell cancers, and seven normal epithelial brushings were determined using a 11,000-element cDNA array. All images were analyzed using BRB ArrayTools. Validation was done using real-time PCR on select genes and immunohistochemical staining. RESULTS: Comparison across endometrial and ovarian cancers and serous and endometrioid tumors showed expression patterns reflecting their organ of origin. Clear cell tumors, however, showed remarkably similar expression patterns regardless of their origin, even when compared with renal clear cell samples. A set of 43 genes was common to comparisons of each of the three histologic subtypes of ovarian cancer with normal ovarian surface epithelium. CONCLUSIONS: The comparison of the gene expression profiles of endometrioid and serous subtypes of ovarian and endometrial cancer are largely unique to the combination of a particular subtype in a specific organ. In contrast, clear cell cancers show a remarkable similarity in gene expression profiles across organs (including kidney) and could not be statistically distinguished.     

Ovarian cancer risk factors by histologic subtypes in the NIH-AARP Diet and Health Study

Data suggest that risk factors for ovarian carcinoma vary by histologic type, but findings are inconsistent. We prospectively evaluated risk factors by histological subtypes of incident ovarian cancer (n = 849) in a cohort of 169,391 women in the NIH-AARP Diet and Health Study. We constructed Cox models of individual exposures by comparing case subtypes to the entire non-case group and assessed p-heterogeneity in case-case comparisons using serous as the reference category. Substantial risk differences between histologic subtypes were observed for menopausal hormone therapy (MHT) use, oral contraceptive (OC) use, parity and body mass index (p-heterogeneity = 0.01, 0.03, 0.05, 0.03, respectively). MHT users were at increased risk for all histologic subtypes except for mucinous carcinomas, where risk was reduced (relative risk (RR) = 0.37; 95% confidence interval (CI): 0.18, 0.80). OC users were only at significantly decreased risk for serous cancers (RR = 0.69; 95% CI: 0.55, 0.85). Although parity was inversely associated with risk of all subtypes, the RRs ranged from 0.28 (clear cell) to 0.83 (serous). Obesity was a significant risk factor only for endometrioid cancers (RR = 1.64; 95% CI: 1.00, 2.70). Our findings support a link between etiological factors and histological heterogeneity in ovarian carcinoma.     

Characterization of ovarian cancer survival by histotype and stage: A nationwide study in Norway

Contemporary population-based data on ovarian cancer survival using current subtype classifications and by surgical status are sparse. We evaluated 1-, 3-, 5- and 7-year relative (and overall) survival, and excess hazards in patients with borderline tumors or invasive epithelial ovarian cancer diagnosed 2012 to 2021 in a nationwide registry-based cohort in Norway. Outcomes were evaluated by histotype, FIGO stage, cytoreduction surgery and residual disease. Overall survival was evaluated for non-epithelial ovarian cancer. Survival of women with borderline ovarian tumors was excellent (≥98.0% 7-year relative survival). Across all evaluated invasive epithelial ovarian cancer histotypes, 7-year relative survival for cases diagnosed with stages I or II disease was ≥78.3% (stage II high-grade serous). Survival for ovarian cancers diagnosed at stage ≥III differed substantially by histotype and time since diagnosis (eg, stage III, 5-year relative survival from 27.7% [carcinosarcomas] to 76.2% [endometrioid]). Overall survival for non-epithelial cases was good (91.8% 5-year overall survival). Women diagnosed with stage III or IV invasive epithelial ovarian cancer and with residual disease following cytoreduction surgery had substantially better survival than women not operated. These findings were robust to restriction to women with high reported functional status scores. Patterns for overall survival were similar to those for relative survival. We observed relatively good survival with early stage at diagnosis even for the high grade serous histotype. Survival for patients diagnosed at stage ≥III invasive epithelial ovarian cancer was poor for all but endometrioid disease. There remains an urgent need for strategies for risk reduction and earlier detection, together with effective targeted treatments.     

Screening for ovarian cancer: what we know, what we need to know

The majority of women with ovarian cancer present with advanced-stage disease. Women with early-stage ovarian cancer have a much better chance of achieving a cure than do women with late-stage disease. This difference makes screening for ovarian cancer, with the hope of detecting it in its presymptomatic state, an attractive concept. Unfortunately, efforts to demonstrate that screening for ovarian cancer in the general population can decrease mortality have been disappointing. Current screening techniques do not have high enough sensitivity and specificity to be applied to the general population, because the low prevalence of the disease in the general population leads to very low positive predictive values for the available screening tests. However, applying current screening strategies to certain high-risk populations (women who carry mutations in the BRCA1 or BRCA2 genes, or with strong family histories of breast/ovarian cancer) is a reasonable approach and may result in acceptably high positive predictive values. This article discusses the results of screening studies using serum CA-125, sonography, other serum markers, and combinations of these tests. Screening for women of average risk is not recommended, although such women should be encouraged to participate in clinical trials whose end points are either the demonstration of the impact of screening on mortality, or the development of novel screening strategies. Screening with twice yearly transvaginal sonography and serum CA-125 testing is recommended for women at high risk for ovarian cancer, although prospective data are needed regarding the impact of such screening on stage of cancer detected, quality of life, and psychological distress, as well as the costs--both personal and societal--of screening.     

Molecular subtypes of breast cancers detected in mammography screening and outside of screening

PURPOSE: The frequency and significance of gene expression profile-derived molecular subtypes of breast cancers found in mammography screening are unknown. EXPERIMENTAL DESIGN: We identified breast cancers diagnosed in women of any age living in defined geographic regions in Finland in 1991 to 1992 and collected clinical and pathologic data. Surrogates for the molecular subtypes were determined for 247 cancers found in organized mammography screening and 989 cancers detected outside of screening using immunohistochemistry or in situ hybridization. Molecular subtypes were defined as luminal A [estrogen receptor (ER) positive and/or progesterone receptor (PR) positive, HER2-], luminal B (ER+ and/or PR+, HER2+), basal-like (ER-, PR-, HER2-, cytokeratin 5+, and/or HER1+), HER2+/ER- (ER-, PR-, and HER2+), and unclassified. The median follow-up time was 9.4 years. RESULTS: The luminal type A was common (73.7%) and the HER2+/ER- type is rare (5.7%) in screen-detected cancer, and only 16% were HER2 positive. Women with cancer diagnosed in screening at ages 50 to 69 years had similar molecular subtype distribution as women whose cancer was found outside of screening at age >69 years. In a multivariate model, cancer detection at screening independently predicted favorable distant disease-free survival when the molecular subtype was included as a covariate in addition to age, histologic grade, and cancer size. Women with small (pT(1)N(0)M(0)) HER2-positive cancer had similar outcome regardless of the method of detection. CONCLUSIONS: Molecular subtype distribution of screen-detected breast cancer differs from that of cancers found outside of screening and accounts in part for the better outcome of screen-detected cancer.     

Using mammographic density to improve breast cancer screening outcomes

It is possible that the performance of mammographic screening would be improved if it is targeted at women at higher risk of breast cancer or who are more likely to have their cancer missed at screening, through more intensive screening or alternative screening modalities. We conducted a case-control study within a population-based Australian mammographic screening program (1,706 invasive breast cancers and 5,637 randomly selected controls). We used logistic regression to examine the effects of breast density, age, and hormone therapy use, all known to influence both breast cancer risk and the sensitivity of mammographic screening, on the risk of small (15 mm) screen-detected and interval breast cancers. The risk of small screen-detected cancers was not associated with density, but the risk of large screen-detected cancers was nearly 3-fold for the second quintile and approximately 4-fold for the four highest density categories (third and fourth quintiles and the two highest deciles) compared with the lowest quintile. The risk of interval cancers increased monotonically across the density categories [highest decile odds ratio (OR), 4.65; 95% confidence interval (95% CI), 2.96-7.31]. The risk of small and large screen-detected cancers, but not interval cancers, increased with age. After adjusting for age and density, hormone therapy use was associated with a moderately elevated risk of interval cancers (OR, 1.43; 95% CI, 1.12-1.81). The effectiveness of the screening program could be improved if density were to be used to identify women most likely to have poor screening outcomes. There would be little additional benefit in targeting screening based on age and hormone therapy use.