Impact of Pre-Operative Breast Magnetic Resonance Imaging (MRI) on Contralateral Synchronous and Metachronous Breast Cancer Detection- A Case Control Comparison Study With Mean Follow-Up of 102 Months.

Background: Women with unilateral breast cancer are at an increased risk for the development of contralateral breast cancers. We hypothesis that combined breast MRI would detect more contralateral synchronous breast cancer than conventional imaging alone, and resulted in less contralateral metachronous breast cancer during follow-up. Methods: In this case control analysis, we retrospectively collected two groups of patients for evaluating the effectiveness and value of adding pre-operative breast MRI to conventional breast images (mammography and sonography) for detection of contralateral synchronous breast cancer. The new metachronous contralateral breast cancer diagnosed during follow-up was prospectively evaluated and compared. Results: Group A (n=733) comprised patients who underwent conventional preoperative imaging and group B (n=735) combined with MRI were enrolled and compared. Seventy (9.5%) of the group B patients were found to have contralateral lesions detected by breast MRI, and 65.7% of these lesions only visible with MRI. The positive predictive value of breast MRI detected contralateral lesions was 48.8%. With the addition of breast MRI to conventional imaging studies, more surgical excisions were performed in contralateral breasts (6% (44/735) versus 1.4% (10/733), P< 0.01), more synchronous contralateral breast cancer detected (2.9% (21/735) versus 1.1% (8/733), P=0.02), and resulted in numerical less (2.2% (16/714) versus 3% (22/725), p=0.3) metachronous contralateral breast cancer during a mean follow-up of 102 months. Conclusions: Combining pre-operative breast MRI evaluation resulted in an increase of contralateral synchronous breast cancer detection, and a numerical less subsequent contralateral metachronous breast cancer occurrence compared to conventional imaging alone. Institutional Review Board, MLO: mediolateral oblique, CC: craniocaudal, BI-RADS: Breast Image Reporting and Data System, ADC: apparent diffusion coecient, VIBE: volumetric interpolated breath-hold examination, CAD: computer aid diagnosis, SD: standard deviation, ER: estrogen receptor, PR: progesterone receptor, HER-2: Human epidermal growth factor receptor-2.

breast cancer detection, and a numerical less subsequent contralateral metachronous breast cancer occurrence compared to conventional imaging alone.

Background
Women with unilateral breast cancer are at an increased risk for the development of contralateral breast cancers, with a 1%-5% incidence of synchronous cancer and a 3%-13% incidence of metachronous cancer [1][2][3][4].
Moreover, women with bilateral breast cancer were found to have worse prognoses than those with unilateral breast cancer [5][6][7]. Methods to enhance early detection of contralateral synchronous breast cancer and/or decrease metachronous contralateral breast cancer would be important for newly diagnosed patients.
However, case control comparison study for evaluation of adding breast MRI to conventional breast imaging for contralateral synchronous breast cancer detection, and the impact of pre-operative MRI to the subsequent occurrence of metachronous contralateral breast cancer was rarely reported [21; 24].
We hypothesis that the high sensitivity of breast MRI would detect more synchronous contralateral breast cancer than conventional imaging group, and resulted in less metachronous contralateral breast cancer found during follow-up. To con rm our hypothesis, we conducted a case control comparison study to evaluate the diagnostic performance of adding pre-operative breast MRI to conventional breast imaging in the detection of synchronous contralateral breast cancer for women with primary operable breast cancer. The incidence, pathology, and management of patients with MRI detected contra-lateral occult breast lesions, impact of ipsilateral and contralateral breast surgery, and new metachronous contralateral breast cancer diagnosed during follow-up were analyzed and reported.

Patients
In this case control comparison analysis, we retrospectively collected two groups of patients for evaluating the effect and value of adding pre-operative breast MRI to conventional breast images (mammography and sonography) for detection of contralateral synchronous breast cancer. A retrospective review of patients who underwent operations for breast cancer from January 2009 to December 2013 was conducted at Changhua Christian Hospital (CCH), a tertiary medical center at central Taiwan. Patients, who diagnosed as primary operable breast cancer, received pre-operative evaluation with conventional breast imaging combined with or without MRI, and received de nite breast cancer operations at CCH were included. Patients who did not receive surgery because of distant metastasis or neoadjuvant chemotherapy were excluded.
The type of operation (breast-conserving surgery (BCS), mastectomy or mastectomy with breast reconstruction), and contralateral breast surgeries were compared. The MRI images and reports were reviewed to identify whether contralateral breast lesions were detected. The subsequent biopsy results and surgical methods were reviewed.
To evaluate the impact of different pre-operative imaging methods on contralateral metachronous breast cancer occurrence, patients were prospectively followed up. Total incidence of recurrence or death due to breast cancer were ascertained at the most recent follow-up, which ended on 30 Sep 2020. The clinicopathologic and imaging data collection was performed by special trained study nurse (SHP), and veri ed by principle investigator (HWL).
This study was approved by the institutional review board (IRB) of CCH (CCH IRB No.140404).

Diagnostic imaging equipment/Conventional breast imaging
Standard mediolateral oblique (MLO) and craniocaudal (CC) views of mammograms were obtained for all patients. Ultrasound procedures were performed with the patient in the supine position. Imaging was performed with a high-resolution 5-12 MHz linear array transducer, including color Doppler ultrasonography (Voluson 530D and 730D). The sonography examinations were carried out by experienced, board-certi ed breast physicians.

MR imaging of study
The MRI protocol used in current study was reported in previous studies [11; 28; 29] and summarized. MR imaging was performed with a Siemens (Verio) 3.0 Tesla magnet. All patients were imaged in the prone position with both breasts placed into a dedicated 16 channel breast coil. The whole breast MRI readings were carried out by experienced, board-certi ed breast radiologist (HKW). All the breast imagines, including mammography, sonography and MRI, were recorded according to the Breast Image Reporting and Data System (BI-RADS) [30].

Statistical Analyses
Data are expressed as mean ± standard deviation (SD) for continuous variables. Independent t tests were used for the comparison of continuous variables. Categorical variables were normally tested by the χ2 test when appropriate. All p values are two-tailed; a p value of less than 0.05 was considered to indicate statistical signi cance. All statistical analyses were performed with SPSS 19.0 software (IBM).

Results
A total of 1468 patients ful lled the inclusion criteria and were enrolled in this study. Patients were strati ed into two preoperative imaging groups. Group A (n = 733) comprised patients who underwent conventional preoperative imaging (mammography and sonography) and group B (n = 735) comprised patients who received MRI combined with conventional imaging (Fig. 1 shows the ow chart of patients' management in the current study). In current case control comparison study, there were no signi cant clinicopathologic differences between patients who received conventional preoperative imaging alone (group A, 733 patients) and those who underwent preoperative MRI (group B, 735 patients) in addition to conventional imaging (Table 1).   (Fig. 1). Compared with the pathology of the 735 primary operable breast cancer (group B), the MRI detected synchronous contra-lateral breast cancer were associated with higher incidence of in situ carcinoma (61.9% versus 15.9%, P < 0.01).
There were no differences in surgical methods (BCS vs mastectomy) employed between the two groups of patients (P = 0.13, Fig. 2 During a mean follow-up of 102 ± 28.6 months, metachronous contralateral breast cancers were found in 22 patients at conventional imaging group, and 16 patients at combined with MRI group (Fig. 3). and compared with literature reviews in Table 3.

Discussion
To evaluate the e cacy of combined breast MRI in the detection of synchronous contralateral breast cancer and the impact of consequent metachronous contralateral breast cancer, we performed a case control comparison study, which enrolled 1468 primary operable breast cancer patients with two different groups of pre-operative breast imaging modalities and received surgery at a single institution, with a mean follow-up of 102 ± 28.6 months. We found that, with the addition of breast MRI to conventional imaging studies, more surgical excisions were performed in contralateral breasts, more synchronous contralateral breast cancer detected, and resulted in numerical less metachronous contralateral breast cancer during follow-up.
In Brennan et al.'s study for evaluation of the contralateral breast cancer detection by pre-operative MRI, the incidence of suspicious MR imaging ndings was 9.3%, with a PPV 47.9%, and a false-positive rate of 52% [31]. In our current study, MR imaging detected 70(9.5%) contralateral lesions in 735 patients, and 21 of them were proved to be malignancy. The PPV of the MRI detected contralateral lesions in our study was 48.8%, which is compatible to literature reported series (Table 3).
The detection of additional abnormal enhancing lesions in breast MRI might be "problematic" for subsequent patient management. Sometimes it is confusing whether these lesions should be ignored, followed up, or referred for biopsy. And the image-guided biopsy before surgery is increasing when breast MRI was incorporated in the pre-operative evaluation [1; 2]. As showed in Fig 1, in the conventional imaging cohort, only 10 (1.4%) patients received contralateral breast surgeries. In the combined MRI group, 44(6%) patients received contralateral breast surgeries when primary index breast cancer surgery was performed (P<0.01). However, the "false positive" rate for the additional lesions detected by MRI is not low as observed in our current study, which around 51.2% of the so called "occult contralateral breast lesions" turned out to be benign neoplasms after surgical excisions (Fig 1), and most of them were broadenomas (34.5%) and brocystic change (43.5%).
Second-look ultrasound and core needle biopsy for suspicious lesion or MRI-guided stereostatic biopsy could obtain tissue diagnosis and decrease unnecessary operations [32]. However, biopsy results of proliferative lesion like papilloma or atypia of the synchronous contralateral lesions were suggested to be excised at the same time when primary index breast cancer operation is performed. As one of our patients was found to have papilloma at core needle biopsy specimen of the contralateral breast lesion, DCIS arising from papilloma was diagnosed in the nal lumpectomy pathology.
Controversies existed that MRI was reported to have increase ipsilateral mastectomy rate and bilateral mastectomy rate [33]. In current case control analysis, the mastectomy rate in the combined MRI cohort of patients was not signi cantly increased when compared with the conventional imaging cohort (52.7% versus 48.6%, P=0.13). The higher number of patients received bilateral mastectomy in combined MRI group were in part due to higher synchronous contralateral breast cancer detection before operation. However, a substantial of patients received bilateral mastectomy due to psychologic stress of the suspicious lesions detected by breast MRI. We also observe a numerical but not statistically signi cant increase of bilateral mastectomy cases in patients received pre-operative evaluation with MRI than conventional imaging only group ( 16.6%), the detected synchronous contralateral breast cancer were associated with higher in situ carcinoma. These ndings could explain why synchronous contralateral breast cancer, which usually presented in an earlier stage than the primary breast cancer [13], was a challenge for clinicians for early detection.
During a mean follow-up of 102±28.6 months, we observed 38 patients developed new metachronous contralateral breast cancer, and 22 (3%) of them were in initial conventional pre-operative imaging group, and 16(2.2%) of them in combined MRI group (Fig 3). Contralateral metachronous cancer could be either synchronous occult cancers not detected by pre-operative imaging and diagnosed during follow-up or could be new contralateral breast cancer developed after initial primary index breast cancer operations. The higher rate of contralateral synchronous breast cancer detected and lower number of contralateral metachronous breast cancer found during follow-up in the pre-operative combined with MRI group (Fig 1, 3) supported the hypothesis that combined with pre-operative MRI could detected more synchronous breast cancer than conventional imaging alone, and during follow-up some occult lesions not detected in contralateral breast at time of primary index cancer operations would be diagnosed as metachronous breast cancer.
Our study was limited due to its retrospective nature and possible selection bias. Patients with contralateral occult lesions detected by conventional imaging alone or combined with MRI did not received surgical excision in every case to con rm the nature of the lesion. This might, therefore, underestimate the actual synchronous breast cancer rate. However, we did collected 733 primary operable breast cancer patients with pre-operative conventional breast imaging, and 735 combined MRI patients who received surgical intervention at a single institution with detailed pathologic report and with a mean follow-up of 102±28. 6

Conclusions
In conclusion, in current case control comparison study, we found an increase of contralateral synchronous breast cancer detection during primary index breast cancer operation and numerical lower number of metachronous contralateral breast cancer occurrence during follow-up in patients with primary operable breast cancer received pre-operative combined MRI evaluation than conventional breast imaging alone. The risk of synchronous contralateral breast cancer should be kept in mind for pre-operative evaluation of primary operable breast cancer patients. Biopsy procedure for tissue diagnosis or surgical strategy discussed with patients is warranted if suspicious synchronous contralateral lesion been detected by conventional imaging and/or breast MRI. Human epidermal growth factor receptor-2.

Declarations
Ethics approval and consent to participate This study was approved by the institutional review board (IRB) of CCH (CCH IRB No.140404) and the need for patient's consent was waived.
Consent for publication