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Digital Breast Tomosynthesis as a Breast Cancer Screening Tool for Women with Gynecologic Cancer

Purpose The purpose of our study was to evaluate digital breast tomosynthesis as a breast cancer screening modality for women with gynecologic cancer. Materials and Methods This retrospective study included patients with underlying gynecologic malignancies who underwent screening digital breast tomosynthesis for breast cancer. The cancer detection rate, recall rate, sensitivity, specificity, and positive predictive value (PPV) were calculated. PPV1 was defined as the percentage of all positive screening exams that have a tissue diagnosis of cancer within a year. PPV2 was defined as the percentage of all diagnostic exams (and Breast Imaging Reporting and Data System category 4, 5 from screening setting) with a recommendation for tissue diagnosis that have cancer within a year. PPV3 was defined as the percentage of all known biopsies actually performed that resulted in a tissue diagnosis of cancer within the year. For each case of screen-detected cancer, we analyzed the age, type of underlying gynecologic malignancy, breast density, imaging features, final Breast Imaging Reporting and Data System assessment, histologic type, T and N stages, molecular subtype, and Ki-67 index. Results Among 508 patients, 7 with breast cancer were identified after a positive result. The cancer detection rate was 13.8 per 1000 screening exams, and the recall rate was 17.9%. The sensitivity was 100%, and the specificity was 83.2%. The false negative rate was 0 per 1000 exams. The PPV1, PPV2, and PPV3 were 7.7, 31.8, and 31.8, respectively. Conclusion Digital breast tomosynthesis may be a promising breast cancer screening modality for women with gynecologic cancer, based on the high cancer detection rate, high sensitivity, high PPV, and high detection rate of early-stage cancer observed in our study.


INTRODUCTION
Mammography as a screening tool has played an essential role in reducing breast cancer mortality. The identification of cancerous lesions by mammography before the lesions are clinically presented can allow early intervention, resulting in long-term survival (1). Despite this advantage, mammography has been criticized due to limited sensitivity, lots of false positive (FP) results, and the risk of overdiagnosis of clinically insignificant lesions (2,3).
The sensitivity of screening mammography for average-risk women has been reported to range from 68% to 88% (4,5). However, screening mammography for high risk groups of breast cancer had a lower sensitivity than average risk groups (6)(7)(8)(9)(10)(11). In recent years, new approaches to breast imaging have been developed. One of them is the use of digital breast tomosynthesis (12). Tomosynthesis acquires multiple projection images from an X-ray source that moves at variable angles in a limited range, and these images are reconstructed into thin slices to reduce the effect of overlapping breast structures. In previous studies (12)(13)(14), the usefulness of digital breast tomosynthesis as a screening test has been demonstrated. However, there was a limited published data on the effectiveness of screening digital breast tomosynthesis for women at high risk of breast cancer (15). But, in the previous study, they did not observe a statistically significant increase in the cancer detection rate compared with the rate of the average-risk group (15).
Patients with underlying gynecologic malignancies also have a higher risk of breast cancer due to well-known gene mutations such as Breast Cancer Susceptibility Gene (BRCA) mutations, hormone effects, and other associated risk factors (16)(17)(18)(19). While there is very few studies on screening digital breast tomosynthesis for high-risk groups of breast cancer, screening digital breast tomosynthesis for only patients with underlying gynecologic malignancies has not been evaluated. Therefore, in this study, we retrospectively reviewed and evaluated the breast cancer detection rates and recall rates among patients with gynecologic cancer (including ovarian cancer, endometrial cancer, and cervical cancer) who underwent screening digital breast tomosynthesis.

IMAGE ACQUISITION AND ANALYSIS
All patients enrolled in our study underwent digital breast tomosynthesis for breast cancer screening. Digital breast tomosynthesis included craniocaudal and mediolateral oblique projections of each breast using a commercially available system (Dimension; Hologic, Bedford, MA, USA). In addition, we obtained synthetic 2D images generated from the digital breast tomosynthesis dataset for each patient using C-View image processing software (Hologic). The device was composed of a custom-designed high-power (mA) tungsten (W) anode X-ray tube with aluminum, rhodium, and silver X-ray filters. The filters produced optimal X-ray spectra based on the thickness and composition of each breast using automatic exposure control.
While the breast was compressed, the X-ray tube moved over a 15° arc, taking serial ultralow-dose mammographs. The average currents for digital breast tomosynthesis were 114 and 56 mA, the tube voltages were 28 and 29 kVp, and the mean glandular doses were 1.2 and 1.5 mGy, respectively.
One of four board-certified radiologists (E.S.C., J.E.L., J.H.K, and J.C.) who had more than 9 years of experience in breast imaging randomly interpreted the digital breast tomosynthesis images. According to the American College of Radiology Breast Imaging Reporting and Data System (ACR BI-RADS) lexicon (20), breast density, imaging features, and final assessments were recorded in the radiologic reports (Table 2). Radiologic findings were based on the original radiographic reports. Based on the ACR BI-RADS lexicon (20), the four categories of

DETERMINATION OF REFERENCE STANDARDS
According to the ACR BI-RADS lexicon (20), negative cases were defined as BI-RADS category 1 or 2, and cases with BI-RADS category 0, 4, or 5 were considered as positive. Negative cases were not suspicious; thus, recall or biopsy was not required. However, positive cases on Percentages may not equal 100 because of rounding.

BI-RADS = Breast Imaging Reporting and Data System
Screening DBT in Gynecological Cancer screening setting included recalled cases. If the cases were initially assessed as BI-RADS category 0, the radiologists recommended recall. As these recalled cases were suspicious, additional imaging was necessary; however, biopsy was not warranted. Positive cases with BI-RADS category 4 or 5 were also suspicious and required both biopsy and recall. Cases with initial BI-RADS category 0, 4, and 5 required tissue confirmation or additional imaging studies including digital mammography and/or breast ultrasonography (US). Final standard references were biopsy and/or surgery. Follow-up imaging was performed for the remaining lesions without biopsy or surgery for at least 1 year. These remaining lesions were considered benign if they were stable on follow-up imaging. In cases of surgery, the T and N stage, hormone receptor expression status, and Ki-67 index were recorded based on the final pathological report.

STATISTICAL ANALYSIS
In the medical audit of breast imaging studies, the main outcome measurements included the sensitivity, specificity, positive predictive value (PPV), recall rate, and cancer detection rate. According to ACR BI-RADS definitions (20)

HISTOLOGY AND IMMUNOHISTOCHEMISTRY
Based on the biopsy or surgical specimens, the histologic type of invasive breast cancer, histologic grade, and axillary lymph node status were determined. The status of estrogen receptor (ER) and progesterone receptor (PR) was scored using the Allred scoring system (21).
The scores were based on the proportion (range, 0-5) and intensity (range, 0-3) of immunostained cells. The total scores (the sum of the proportion and intensity scores) were in the range of 0-8. The positivity of ER or PR was defined as a total score of more than 2. The expression status of human epidermal growth factor receptor-2 (Her-2) was initially determined by immunohistochemical staining. According to the proportion and the intensity of cell membrane staining, the Her-2 expression was scored (0, ≥ 1, ≥ 2, and ≥ 3) and grouped as negative (0, ≥ 1, and ≥ 2) or positive (≥ 3). For the Ki-67 index, a nuclear staining of 14% or more indicated a high level of expression (22). Based the hormone receptor expression sta-

RADIOLOGIC FINDINGS
Between July 2013 and July 2017, the number of digital breast tomosynthesis for each patient ranged from 1 to 5. Only initial imaging was performed for 377 patients (74.2%). On the other hand, imaging was performed two times for 114 patients (22.4%) and three times for 17 patients (3.3%). In this study, 508 cases were categorized based on the breast composition, imaging features, and initial BI-RADS assessment ( Table 2). The breast composition was classified into four groups based on ACR BI-RADS definitions (20). The majority of patients (207 patients) had heterogeneously dense breasts. The number of patients with denser breasts (including heterogeneously dense breasts and extremely dense breasts) was slightly higher than that of the other patients (including almost fatty breasts and scattered fibroglandular breasts). More than half of the patients with positive findings had a mass or asymmetry without calcification. In the initial BI-RADS assessment, 80 patients (15.7%) were considered as category 0 (Table 2). Additional US was performed for 70 of them, and additional magnification views were taken for 9 of them; only 1 patient had both. Table 3 summarizes the results of screening exams using digital breast tomosynthesis for 508 patients with underlying gynecologic malignancies. The Table 3 Table 4 shows a summary of screen-detected cancers including the patient's age, type of un-  with screen-detected cancer, the age range was 39-59 years, and the mean age was 49.9 years, which was lower than the average age of all patients (n = 508). Overall, 4 patients had cervical cancer, 2 patients had endometrial cancer, and 1 patient had ovarian cancer. All patients belonged to the scattered fibroglandular group or heterogeneous dense group of breast density.

SCREEN DETECTED CANCERS
All cases of invasive breast cancer were detected in patients with denser breasts but not patients with less dense breasts. The radiologic findings of 4 patients were a mass or asymmetry.
Calcification only was observed for 2 patients, and a mass or asymmetry with calcification was observed for 1 patient (Fig. 1)

DISCUSSION
According to the American Cancer Society (ACS), women with a high risk of breast cancer are defined as women with genetics-based increased risk (and their untested first-degree relatives), women with a calculated lifetime risk of 20% or more or a history of chest radiation therapy at a young age, women with personal histories of breast cancer and dense tissue or those diagnosed by age 50, and women with atypia at biopsy (23). However, patients with gynecologic cancer also have a higher risk of breast cancer (16)(17)(18)(19). BRCA mutations, which are well-known gene mutations that result in a high risk of breast cancer, also contribute to predisposition to ovarian cancer. In addition to BRCA mutations, mutations in the CHEK2, ATM, and PALB2 genes have been reported as risk factors of breast cancer and ovarian cancer (16).
Hereditary nonpolyposis colorectal cancer or Lynch syndrome is an autosomal dominant genetic disorder that is associated with endometrial and ovarian cancer. Some breast cancers are associated with Lynch syndrome (16,17). Peutz-Jeghers syndrome is an autosomal dominant genetic disorder that can increase the risk of developing carcinomas of the breasts, ovaries, and uterus and sex cord-stromal tumors with annular tubules in the ovaries (18). In addition to genetic factors, hormone effects such as late menopause, late age at first childbirth, and common risk factors such as obesity can affect the risk of breast and gynecologic cancers (19). Therefore, for patients with gynecologic cancer, the research to find suitable screening tool is needed.
In previous studies (6)(7)(8)(9)(10)(11), it was found that women with a high risk of breast cancer based on their family history or genetic testing could benefit strongly from breast MRI. Furthermore, in comparison with mammography and/or US, screening breast MRI for women with a high risk of breast cancer has a significantly higher cancer detection rate, higher sensitivity, and lower interval invasive cancer rate (6)(7)(8)(9)(10)(11). According to the ACS, supplemental breast MRI after conventional mammography is recommended as a screening tool adjunctive to mammography for women with a high risk of breast cancer (24). However, breast MRI as a screening tool has several disadvantages (25). It can lead to too many positive imaging findings including clinically insignificant lesions. In addition, screening breast MRI requires an extended period of time, which may disrupt the schedule of patients, technologists, and radiologists. The biggest obstacle is that breast MRI is too expensive to conduct annually. Therefore, breast MRI should be replaced with a suitable alternative. In contrast to breast MRI, digital breast tomosynthesis is a practical and time-saving approach; thus, many radiologists have recommended digital breast tomosynthesis as a screening modality for patients with an average risk.
Previous studies have reported that digital breast tomosynthesis plus conventional screening mammography could reduce the recall rate for additional imaging and increase breast cancer detection (14,15). According to recommended benchmarks for screening mammography interpretations from the Breast Cancer Surveillance Consortium (BCSC) using 401548 populations because of the relatively low sensitivity and significantly higher interval invasive cancer rate (6)(7)(8)(9)(10)(11). Therefore, the high sensitivity observed in our study demonstrated the advantage of the screening tool compared with conventional mammography.
The potential benefit of digital breast tomosynthesis is higher sensitivity in dense breasts rather than conventional mammography (27). In this study, the breast density was lower than that of Korean population (28,29), so the benefit of this DBT might be less reflected. The lower breast density of our groups may be caused due to hormone suppression therapy for gyne- Although digital breast tomosynthesis has been suggested to reduce the recall rate, our recall rate was rather high (17.9%). This value was higher than that of previous studies (6.1-9.2%) (15,30,31). It should be noted that the published data were based on an average-risk population, whereas our recall rate was based on a high-risk population. Because the estimated value of our positive results was higher than average-risk groups, our recall rate might be increased. Moreover, this study was conducted in a specialized academic center and not a local hospital, which could result in a selection bias and a higher recall rate. Other studies have reported that recall rates in screening MRI range from 8% to 16% (7,8,10,32,33). Although these studies were performed with high-risk populations, their lower recall rate compared with the rate in our study might be associated with BI-RADS category 0. In BI-RADS assessment, it is recommended to avoid category 0 in breast MRI after screening mammography. However, there is no such restriction for screening digital breast tomosynthesis. In our study, the num-Screening DBT in Gynecological Cancer ber of BI-RADS category 0 cases accounted for more than half of the number of abnormal interpretations. There are some limitations in our study. First, our results were reviewed retrospectively, and this study was performed at a single, large academic center equipped with specialized breast imagers; these factors may cause bias. The second limitation is the lack of genetic information. Tests for genetic mutations are costly if they are not covered by the national health insurance system. Among 508 patients, only 19 patients underwent genetic testing for BRCA mutations; 4 of them were BRCA1 mutation carriers, and 1 of them were BRCA2 mutation carriers. Third limitation is too short follow-up data (at least 2 year) to observe interval cancer. However, digital breast tomosynthesis is emerging modality, thus almost previous studies for screening digital breast tomosynthesis have at least 1 year follow-up period (12-15, 28, 34, 35). Screening breast MRI is recommended for women with a high risk of breast cancer.
However, because of the retrospective study design, we cannot directly compare the performance measures of screening breast MRI. Future studies should be performed prospectively in a multicenter setting with sufficient genetic information about the risk of breast cancer. And future studies are needed for the long-term follow-up period.
In conclusion, digital breast tomosynthesis may be a promising breast cancer screening modality for women with gynecologic cancer based on the high cancer detection rate, high sensitivity, high PPV, and high detection rate of early-stage cancer observed in our study.

Conflicts of Interest
The authors have no potential conflicts of interest to disclose.