Frequency and characteristics of contralateral breast abnormalities following recall at screening mammography

This is a prospective observational follow-up study of women aged 50-75 who attended a biennial breast cancer screening programme conducted in the south of The Netherlands. A consecutive series of 130,338 full-field digital mammography screens (13,762 initial screens and 116,576 subsequent screens) between 1 January 2014 and 1 January 2016 were included. The screening mammograms were obtained at four specialised screening units in a biennial screening mammography programme conducted in the south of The Netherlands.

Women are personally invited by letter to attend the screening programme. These letters are sent to the address of every woman aged between 50 and 75 years old registered in the municipal registration. Women being treated for breast cancer or those attending clinical follow-up after treatment of breast cancer do not attend the screening programme. Otherwise, there are no exclusion criteria for screening eligibility.

Women participating in our screening mammography programme were asked for permission to use their data for scientific purposes and for the evaluation of the screening programme. All women gave permission to use their screening and diagnostic data.

Possible exclusion criteria included no permission to use screen data, technical failure of screening equipment and insufficient image quality as assessed by an experienced screening radiologist. None of the women screened for study inclusion met these criteria.

A total of 3,995 women were recalled for further analysis. The hospitals involved in these recalls were visited and data as described below were obtained. Possible exclusion criteria after recall included insufficient follow-up or loss to follow-up, incomplete records, no permission to access data. None of the women recalled for analysis met these criteria and no recalls were excluded from analysis.

Ethical approval by our local Institutional Review Board was not required for this prospective observational follow-up study, according to the Dutch Central Committee on Research involving Human Subjects (CCMO).

Details of our breast cancer screening programme have been described previously [14]. In brief, the mammography screening programme in The Netherlands is a nationwide programme that provides free biennial screening mammography for women aged 50-75 years. Women are personally invited for screening and the attendance rate is more than 80%. Before each screening examination, the woman completes a short questionnaire with questions about previous recalls and any previous breast surgery or breast malignancy.

All digital mammograms were obtained with a Lord Selenia FFDM system (Hologic, Danbury, CT, USA), with a 70-μm pixel size and a 232 × 286-mm field of view. The examinations were obtained by specialised screening mammography radiographers and all screening mammograms were double-read in a blinded fashion by a team of 12 certified screening radiologists. Each radiologist evaluated at least 3,000 mammograms yearly.

The screening radiologists classified abnormal mammographic findings into one of the following categories: suspicious mass, suspicious calcifications, suspicious mass in combination with calcifications, architectural distortion, asymmetry or other. Each screen was then classified according to the BIRADS lexicon [15]. Women with a BI-RADS 1 or 2 were not recalled and women with a BI-RADS 0, 4 or 5 were referred to a dedicated breast unit of a hospital for further analysis of their mammographic finding. The BI-RADS category 3 is not applied as short-term follow-up is not available in the Dutch screening programme.

Although a total of 20 hospitals were involved in the diagnostic work-up of recalled women, the diagnostic work-up in the majority of women (97.2%, 3,883/3,995) was performed in seven regional hospitals. All recalled women underwent physical examination by a surgical oncologist or dedicated breast nurse and received additional evaluation at the radiology department. A radiologist first reassessed the screening mammogram of both breasts, which was routinely available and stored in the Picture Archiving and Communication System (PACS) of the hospital. Additional imaging was obtained at the discretion of the radiologist after this review. Full-field digital mammography was available in each of the seven regional hospitals. Breast tomosynthesis was present in two hospitals from the beginning of the inclusion period and became available in three others in 2015. Breast ultrasonography was used for the further characterisation of mammographic abnormalities and palpable breast lesions, for biopsy guidance and for target or second look purposes following breast MRI. Whole-breast ultrasonography was not encouraged, in accordance with the Dutch guidelines [16]. Breast MRI was also available in each of the seven hospitals and performed if indicated, as defined by the guidelines of the European Society of Breast Imaging [17] and the Dutch guidelines. Fine-needle aspiration biopsy (FNAB), core-needle biopsy (CNB) and stereotactic biopsy were performed in each of the seven hospitals, whereas MRI guided biopsy procedures were concentrated in the larger hospitals. All recalls were discussed by multidisciplinary teams that consisted of surgical oncologists, radiologists, medical oncologists, radiation oncologists, plastic surgeons, breast nurses and breast radiographers.

During 1-year follow-up, clinical data and data from diagnostic breast imaging, biopsy specimen and surgical procedures were collected of all recalled women. Information on breast density, hormonal replacement therapy and family history of breast cancer were also extracted from the screening records and clinical data. Breast cancers were categorised into ductal carcinoma in situ (DCIS) and invasive cancers; lobular carcinoma in situ was considered a non-malignant lesion. The TNM (tumour, nodes and metastases) classification was used for malignant lesions [18]. For all cancers treated by neo-adjuvant therapy (either chemotherapy or anti-hormonal therapy), tumour size was derived from breast imaging (usually MRI) prior to the start of this therapy.

The methods of detection and subsequent assessment of contralateral breast lesions were derived from the clinical records and clinical radiology reports. Similar to the work-up of screen-detected mammographic abnormalities, biopsy data and surgical reports of contralateral breast lesions were obtained.

Two screening radiologists reviewed the latest screening mammogram of each woman with a cancer diagnosed in the contralateral breast. They classified the cancer as missed, minimal sign or occult at the previous screen according to the European guidelines [19, 20].

Descriptive statistics were performed using Statistical Package for Social Science 23.0 (SPSS IBM, Chicago, IL, USA). The chi-squared test was used to test for differences between women without and with additional contralateral breast lesions detected following recall. A p value of less than 0.05 was considered to indicate a statistically significant difference. The p values were two sided.

There was no loss to follow-up. In a small number of cases, data were missing (e.g. oestrogen or progesterone receptor status missing due to an insufficient tissue sample). Statistical correction was not performed for the very small numbers of missing data, and data missing was considered to be at random.

Bias was not expected in recall of women who attended screening. In the diagnostic setting, several types of bias may occur, especially observer bias and detection bias, but statistical correction for this type of bias is not feasible in this study. Selection bias was considered highly unlikely as all women analysed in the diagnostic setting were included for statistical analysis.

The mean age of the 130,338 consecutively screened women was 59.6 years (95% CI, 59.4-59.8 years) and 8.2% reported to have had previous breast surgery. A total of 3,995 (3.1%) were recalled for further assessment. Breast cancer was diagnosed in 905 recalled women [including 163 (18.0%) ductal carcinoma in situ], resulting in an overall cancer detection rate of 6.9 per 1,000 screens [initial screens, 8.6 (118/13,762); subsequent screens, 6.8 (787/116,576)] and an overall positive predictive value (PPV) of recall of 22.7% [initial screens, 11.4% (118/1,037); subsequent screens, 26.6% (787/2,958)]. A patient flow chart is provided in Fig. 1.

A total of 129 women, 3.2% of all recalls, underwent assessment of a contralateral breast abnormality that was detected after recall. Baseline characteristics of recalled women, with or without analysis of a contralateral non-recalled lesion, are shown in Table 1. These characteristics were similar for both groups except for a higher breast density (III + IV) in women assessed for a contralateral breast lesion when compared to a recalled breast lesion (38.8% and 23.8% respectively, p < 0.001).

The contralateral abnormality was detected at clinical mammography and/or breast tomosynthesis in 101 women and at breast MRI in 23 women. In the remaining five women, the contralateral breast was evaluated due to the presence of a suspicious finding at clinical breast examination by the surgical oncologist or breast nurse (palpable breast lesion, four cases; Paget disease of the nipple, one case).

The mammographic characteristics of the contralateral lesions detected at clinical mammography (with/without tomosynthesis) were as follows: suspicious mass, 90; suspicious calcifications, 8; suspicious mass with calcifications, 1; architectural distortion, 2. The indications for breast MRI in the 23 women with a contralateral lesion detected at MRI had been as follows: problem solving of the recalled lesion, 9 women; determination of tumour size and/or multifocality/multicentricity of a screen detected malignancy, 10 women; invasive lobular cancer, 4 women. Breast MRI showed a suspicious mass or non-mass enhancement in 19 women and 4 women, respectively.

The majority of women with an abnormality detected in the contralateral breast underwent only breast imaging for the further evaluation of these lesions (Table 2). A total of 74 women (57.4%) received breast ultrasonography and the remaining 55 women (42.6%) underwent one or several percutaneous and/or excisional biopsy procedures to establish a final pathological diagnosis.

Of the 129 lesions detected in the contralateral breast, 20 (15.5%) proved to be malignant (Table 3). The majority of the malignancies presented themselves as a suspicious mass at clinical mammography (eight cases, 47.1%) or breast MRI (seven cases, 41.2%). Of the nine contralateral breast cancers detected at mammography, two were visible only at breast tomosynthesis and not at the full-field digital mammogram. Of the seven cancers visible at the latest screening mammogram in retrospect, respectively four were considered to be missed and three showed a minimal sign. As mentioned previously, the remaining three contralateral cancers presented as palpable breast lesions, not primarily detected at breast imaging. In 16 of the 20 women with a breast cancer diagnosed in the contralateral breast, the mammographic abnormality at screening turned out to be malignant as well, resulting in 16 bilateral cancer cases. In the four remaining cases, the contralateral lesion turned out to be malignant, and the mammographic abnormality at screening turned out to be benign. One of these cases is presented in Fig. 2. The majority of benign lesions detected in the contralateral breast comprised cysts (52.3%, 57/109) and fibroadenomas (13.8%, 15/109).

Of the recalled lesions and contralateral, non-recalled lesions, respectively 22.6% and 15.5% proved to be malignant (p = 0.06; Table 4). The type of assessment after recall (clinical breast imaging versus biopsy in addition to clinical breast imaging) was similar for both groups. The positive predictive value of biopsy, however, was higher for recalled lesions (53.1% vs 36.4%, p = 0.01). The tumour characteristics and final surgical treatment of unilateral, screen-detected cancers were similar with those of cancers diagnosed in the contralateral, non-recalled breast (Table 5).