Objective

Studies of cancer screening have found that false positive screening events (FPSE) can affect worry about cancer risk and screening program use, we sought to further explore this.

Method

In a study of 1,100 women at high risk for ovarian cancer who participated in a previously published randomized controlled trial (RCT), we sought to explore whether worry might also influence the use of risk-reducing surgical procedures by women. Participants included 234 women with BRCA1/2 mutations and 866 women with high-risk pedigrees. We followed the women for up to 6 years.

Results

Worry predicted risk reducing prophylactic bilateral salpingo-oophorectomy (pBSO) for both mutation carriers (HR = 1.74; p = .02), and women with high-risk pedigree (HR = 3.41; p < .001). FPSE also predicted subsequent pBSO among women with a high-risk pedigree (HR 2.31; p < .01). While screening may reduce worry among those who never receive a positive result, FPSE increase worry at least temporarily. Worry about ovarian cancer risk predicted use of preventative pBSO among high-risk women including those with BRCA1/2 mutations enrolled in an ovarian cancer-screening program. FPSE also predicted risk-reducing ovarian surgery among high-risk women without a known mutation at the time of screening program enrollment.

Conclusions

Physicians who offer screening should know that false positive results may increase use of pBSO, how this should effect clinical practice is unclear. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

This study was initiated to identify biomarkers with potential value for the early detection of poor-outcome breast cancer. Two sets of well-characterized tissues were utilized: one from breast cancer patients with favorable vs. poor outcome and the other from healthy women undergoing reduction mammaplasty. Over 46 differentially expressed genes were identified from a large list of potential targets by a) mining publicly available expression data (identifying 134 genes for quantitative PCR) and b) utilizing a commercial PCR array. Three genes show elevated expression in cancers with poor outcome and low expression in all other tissues, warranting further investigation as potential blood markers for early detection of cancers with poor outcome. Twelve genes showed lower expression in cancers with poor outcome than in cancers with favorable outcome but no differential expression between aggressive cancers and most healthy controls. These genes are more likely to be useful as prognostic tissue markers than as serum markers for early detection of aggressive disease. As a secondary finding was that, when histologically normal breast tissue was removed from a distant site in a breast with cancer, 7 of 38 specimens displayed a cancer-like expression profile, while the remaining 31 were genetically similar to the reduction mammaplasty control group. This finding suggests that some regions of ipsilateral histologically 'normal' breast tissue are predisposed to becoming malignant and that normal-appearing tissue with malignant signature might warrant treatment to prevent new primary tumors.

Background

Serum markers are used before pelvic imaging to improve specificity and positive predictive value (PPV) of ovarian cancer multimodal screening strategies.

Methods

We conducted a randomized controlled pilot trial to estimate surgical PPV of a "2 of 3 tests positive" screening rule, and to compare use of HE4 as a first-line (Arm 1) versus a second-line (Arm 2) screen, in women at high and elevated risk for epithelial ovarian cancer (EOC) at five study sites. Semiannual screening was offered to 208 women ages 25 to 80 years with deleterious BRCA germline mutations and to 834 women ages 35 to 80 years with pedigrees suggesting inherited susceptibility. Annual screening was offered to 130 women ages 45 to 80 years (Risk Group 3) with epidemiologic and serum marker risk factors. Rising marker levels were identified using the parametric empirical Bayes algorithm.

Results

Both strategies yielded surgical PPV above 25%. Protocol-indicated surgery was performed in 6 women, identifying two ovarian malignancies and yielding a surgical PPV in both arms combined of 33% (95% confidence interval: 4%-78%), 25% in Arm 1 and 50% in Arm 2. Surgical consultation was recommended for 37 women (26 in Arm 1 and 11 in Arm 2). On the basis of 12 women with at least 2 of 3 tests positive (CA125, HE4, or imaging), an intent-to-treat analysis yielded PPV of 14% in Arm 1 and 20% in Arm 2.

Conclusions

Positive screens were more frequent when HE4 was included in the primary screen.

Impact

HE4 may be useful as a confirmatory screen when rising CA125 is used alone as a primary screen.

Objective

We developed and validated a hybrid risk classifier combining serum markers and epidemiologic risk factors to identify post-menopausal women at elevated risk for invasive fallopian tube, primary peritoneal, and ovarian epithelial carcinoma.

Methods

To select epidemiologic risk factors for use in the classifier, Cox proportional hazards analyses were conducted using 74,786 Women's Health Initiative (WHI) Observational Study (OS) participants. To construct a combination classifier, 210 WHI OS cases and 536 matched controls with serum marker measurements were analyzed; validation employed 143 cases and 725 matched controls from the WHI Clinical Trial (CT) with similar data.

Results

Analyses identified a combination risk classifier composed of two elevated-risk groups: 1) women with CA125 or HE4 exceeding a 98% specificity threshold; and 2) women with intact fallopian tubes, prior use of menopausal hormone therapy for at least two years, and either a first degree relative with breast or ovarian cancer or a personal history of breast cancer. In the WHI OS population, it classified 13% of women as elevated risk, identifying 30% of ovarian cancers diagnosed up to 7.8years post-enrollment (Hazard Ratio [HR]=2.6, p<0.001). In the WHI CT validation population, it classified 8% of women as elevated risk, identifying 31% of cancers diagnosed within 7years of enrollment (HR=4.6, p<0.001).

Conclusion

CA125 and HE4 contributed significantly to a risk prediction classifier combining serum markers with epidemiologic risk factors. The hybrid risk classifier may be useful to identify post-menopausal women who would benefit from timely surgical intervention to prevent epithelial ovarian cancer.