Breast Cancer Mortality among Women with a BRCA1 or BRCA2 Mutation in a Magnetic Resonance Imaging Plus Mammography Screening Program.

Annual breast magnetic resonance imaging (MRI) plus mammography is the standard of care for screening women with inherited BRCA1/2 mutations. However, long-term breast cancer-related mortality with screening is unknown. Between 1997 and June 2011, 489 previously unaffected BRCA1/2 mutation carriers aged 25 to 65 years were screened with annual MRI plus mammography on our study. Thereafter, participants were eligible to continue MRI screening through the high-risk Ontario Breast Screening Program. In 2019, our data were linked to the Ontario Cancer Registry of Cancer Care Ontario to identify all incident cancers, vital status and causes of death. Observed breast cancer mortality was compared to expected mortality for age-matched women in the general population. There were 91 women diagnosed with breast cancer (72 invasive and 19 ductal carcinoma in situ (DCIS)) with median follow-up 7.4 (range: 0.1 to 19.2) years. Four deaths from breast cancer were observed, compared to 2.0 deaths expected (standardized mortality ratio (SMR) 2.0, p = 0.14). For the 489 women in the study, the probability of not dying of breast cancer at 20 years from the date of the first MRI was 98.2%. Annual screening with MRI plus mammography is a reasonable option for women who decline or defer risk-reducing mastectomy.

Differences in natural history between breast cancers in BRCA1 and BRCA2 mutation carriers and effects of MRI screening-MRISC, MARIBS, and Canadian studies combined.

BACKGROUND: It is recommended that BRCA1/2 mutation carriers undergo breast cancer screening using MRI because of their very high cancer risk and the high sensitivity of MRI in detecting invasive cancers. Clinical observations suggest important differences in the natural history between breast cancers due to mutations in BRCA1 and BRCA2, potentially requiring different screening guidelines. METHODS: Three studies of mutation carriers using annual MRI and mammography were analyzed. Separate natural history models for BRCA1 and BRCA2 were calibrated to the results of these studies and used to predict the impact of various screening protocols on detection characteristics and mortality. RESULTS: BRCA1/2 mutation carriers (N = 1,275) participated in the studies and 124 cancers (99 invasive) were diagnosed. Cancers detected in BRCA2 mutation carriers were smaller [80% ductal carcinoma in situ (DCIS) or ≤10 mm vs. 49% for BRCA1, P < 0.001]. Below the age of 40, one (invasive) cancer of the 25 screen-detected cancers in BRCA1 mutation carriers was detected by mammography alone, compared with seven (three invasive) of 11 screen-detected cancers in BRCA2 (P < 0.0001). In the model, the preclinical period during which cancer is screen-detectable was 1 to 4 years for BRCA1 and 2 to 7 years for BRCA2. The model predicted breast cancer mortality reductions of 42% to 47% for mammography, 48% to 61% for MRI, and 50% to 62% for combined screening. CONCLUSIONS: Our studies suggest substantial mortality benefits in using MRI to screen BRCA1/2 mutation carriers aged 25 to 60 years but show important clinical differences in natural history. IMPACT: BRCA1 and BRCA2 mutation carriers may benefit from different screening protocols, for example, below the age of 40.

Is ductal carcinoma in situ with "possible invasion" more predictive of invasive carcinoma than pure ductal carcinoma in situ?

OBJECTIVES: To compare the underestimation of ductal carcinoma in situ (DCIS) vs DCIS with "possible invasion" at breast biopsy and to determine if any factors related to clinical indication, imaging abnormality, biopsy, or DCIS-grade affected the likelihood of underestimation. METHODS: Of 3836 consecutive lesions that were biopsied by using a 14-gauge needle, 117 lesions revealed DCIS. Surgical pathology results of invasive carcinoma were compared with needle biopsy results of DCIS or DCIS with possible invasion. Clinical indication, imaging abnormality, biopsy guidance modality, sample number, and histologic grade were recorded. Yates corrected χ(2) and Fisher exact tests were used to determine differences between groups. RESULTS: A total of 101 lesions were DCIS and 16 were DCIS with possible invasion at biopsy. Thirty-six of 117 lesions (31%) revealed invasive carcinoma at resection pathology. Invasive carcinoma was present more often when DCIS with possible invasion was diagnosed compared with pure DCIS (7/16 [44%] vs 29/101 [29%], P = .36). No factor, including clinical indication, imaging abnormality, biopsy guidance method, sample number, or grade, was found to significantly affect the likelihood of underestimation for lesions diagnosed as DCIS vs DCIS with "possible invasion." The likelihood of pure DCIS underestimation significantly increased when lesions were high grade compared with either intermediate or low grade (18/44 [41%] vs 9/44 [21%] vs 2/10 [20%], P = .03). CONCLUSION: For lesions biopsied by using a 14-gauge needle, there is a trend towards underestimation of the presence of invasive carcinoma when pathology reveals DCIS with possible invasion compared with pure DCIS. High-grade DCIS was significantly more likely to be underestimated.

Psychological impact of recall on women with BRCA mutations undergoing MRI surveillance.

OBJECTIVE: The addition of magnetic resonance imaging (MRI) to mammography for surveillance of women with BRCA mutations significantly increases sensitivity but lowers specificity. This study aimed to examine whether MRI surveillance, and particularly recall, is associated with increased anxiety, depression, or breast cancer worry/distress. METHODS: Women with BRCA mutations in an MRI surveillance study were invited to complete: Hospital Anxiety and Depression Scale (HADS), Lerman's Breast Cancer Worry Scale, Breast Cancer Worry Interference Scale, and a quality of life rating at 3 time points: 1-2 weeks before (T1), 4-6 weeks after (T2) and 6 months after their annual surveillance (T3). Repeated measures analyses were performed over the 3 time points for recalled and non-recalled women. RESULTS: 55 women (30 BRCA1, 25 BRCA2) completed study instruments at T1 and T2, and 48 at T3. Eighteen women (32%) were recalled for additional imaging. At T1, 27 women (49%) were above HADS threshold for "possible cases" for anxiety (score≥8). Recalled (but not non-recalled) women had a significant increase of HADS anxiety at T2 which dropped to below baseline by T3. No group differences were observed in terms of change over time in other quantitative psychological measures. CONCLUSIONS: While breast MRI surveillance did not have a detrimental psychological impact on women with a BRCA1 or BRCA2 mutation, recalling these very high-risk women for further imaging after a false positive MRI scan temporarily increased their global anxiety.

Improvement in DCIS detection rates by MRI over time in a high-risk breast screening study.

Although magnetic resonance imaging (MRI) is much more sensitive than mammography for detecting early invasive breast cancer, in many high-risk screening studies MRI was less sensitive than mammography for detecting ductal carcinoma in situ (DCIS). We reviewed our experience detecting DCIS in our single center study of annual MRI, mammography, ultrasound and clinical breast examination (CBE) for screening very high-risk women. All cases of DCIS±microinvasion and invasive cancer were compared in two time frames: before (period A) and after (period B) July 2001-when we acquired expertise in the detection of DCIS with MRI-with respect to patient demographics, method of detection, and rates of detection of invasive cancer and DCIS. In period A there were 15 cases (3.1% of 486 screens) in 223 women, of which 2 (13%) were DCIS-one with microinvasion-neither detected by MRI. In period B there were 29 cases (3.3% of 877 screens) in 391 women, of which 10 (34%) were DCIS±microinvasion (p=0.04), all 10 detected by MRI but only one by mammography. No DCIS cases were detected by ultrasound or CBE. Specificity was lower in period B than in period A but acceptable. The ability to detect DCIS with screening MRI improves significantly with experience. MRI-guided biopsy capability is essential for a high-risk screening program. In experienced centers the increased sensitivity of MRI relative to mammography is at least as high for DCIS as it is for invasive breast cancer.

Preoperative breast magnetic resonance imaging: controversies arising in the quest to evaluate clinical benefit.

Breast magnetic resonance imaging (MRI) is indisputably the highest sensitivity test available to detect breast cancer, revealing more extensive cancer in the ipsilateral and otherwise occult cancer in the contralateral breasts when used before surgery. The use of preoperative breast MRI has become somewhat controversial, because the clinical benefit of the heightened detection provided by MRI has been questioned in the context of multidisciplinary breast cancer treatment, relatively low local recurrence, and metachronous contralateral cancer rates. Also, MRI detection rates have been compared with the high rates reported in the pathology literature. The emerging clinical outcome literature is showing conflicting results to demonstrating actual overall benefit. Critical review of this literature reveals several misconceptions about MRI detection rates and limitations of many of the published outcome studies to date, which render the results not necessarily generalizable to contemporary optimized breast MRI practices. This article addresses some of the misconceptions raised by critics, provides a critical review of the clinical outcome literature, reviews patient subgroups anticipated to have the highest yield when using preoperative MRI, makes recommendations for optimizing breast MRI practice, and suggests areas for potential future research.

Preliminary in vivo validation of a dedicated breast MRI and sonographic coregistration imaging system.

OBJECTIVE: Sonographic correlation of breast MRI findings is often challenging. We present a preliminary in vivo feasibility study evaluating the degree of error of a new MRI-sonography coregistration system for showing MRI and sonographically visible breast lesions. CONCLUSION: In 10 patients with 13 lesions, the system was found to be an accurate means for targeting sonography to MRI of the same breast lesions.

Is mammography adequate for screening women with inherited BRCA mutations and low breast density?

BACKGROUND: Several observational studies have shown that magnetic resonance imaging (MRI) is significantly more sensitive than mammography for screening women over age 25 at high risk for hereditary breast cancer; however, MRI is more costly and less specific than mammography. We sought to determine the extent to which the low sensitivity of mammography is due to greater breast density. METHODS: Breast density was evaluated for all patients on a high-risk screening study who were diagnosed with breast cancer between November 1997 and July 2006. Density was measured in two ways: qualitatively using the four categories characterized by the Breast Imaging Reporting and Data System and quantitatively using a computer-aided technique and classified as (a) 50% density. Comparison of sensitivity of mammography (and MRI) for each individual density category and after combining the highest two and lowest two density categories was done using Fisher's exact test. RESULTS: A total of 46 breast cancers [15 ductal carcinoma in situ (DCIS) and 31 invasive] were diagnosed in 45 women (42 with BRCA mutations). Mean age was 48.3 (range, 32-68) years. Overall, sensitivity of mammography versus MRI was 20% versus 87% for DCIS and 26% versus 90% for invasive cancer. There was a trend towards greater mammographic sensitivity for invasive cancer in women with fattier breasts compared with those with greater breast density (37-43% versus 8-12%; P = 0.1), but this trend was not seen for DCIS. CONCLUSION: It is necessary to add MRI to mammography for screening women with BRCA mutations even if their breast density is low.

BRCA1 mutation and young age predict fast breast cancer growth in the Dutch, United Kingdom, and Canadian magnetic resonance imaging screening trials.

PURPOSE: Magnetic resonance imaging (MRI) screening enables early detection of breast cancers in women with an inherited predisposition. Interval cancers occurred in women with a BRCA1 mutation, possibly due to fast tumor growth. We investigated the effect of a BRCA1 or BRCA2 mutation and age on the growth rate of breast cancers, as this may influence the optimal screening frequency. EXPERIMENTAL DESIGN: We reviewed the invasive cancers from the United Kingdom, Dutch, and Canadian MRI screening trials for women at hereditary risk, measuring tumor size at diagnosis and on preceding MRI and/or mammography. We could assess tumor volume doubling time (DT) in 100 cancers. RESULTS: Tumor DT was estimated for 43 women with a BRCA1 mutation, 16 women with a BRCA2 mutation, and 41 women at high risk without an identified mutation. Growth rate slowed continuously with increasing age (P = 0.004). Growth was twice as fast in BRCA1 (P = 0.003) or BRCA2 (P = 0.03) patients as in high-risk patients of the same age. The mean DT for women with BRCA1/2 mutations diagnosed at ages < or =40, 41 to 50, and >50 years was 28, 68, and 81 days, respectively, and 83, 121, and 173 days, respectively, in the high-risk group. Pathologic tumor size decreased with increasing age (P = 0.001). Median size was 15 mm for patients ages < or =40 years compared with 9 mm in older patients (P = 0.003); tumors were largest in young women with BRCA1 mutations. CONCLUSION: Tumors grow quickly in women with BRCA1 mutations and in young women. Age and risk group should be taken into account in screening protocols.

Incidental MRI detection of BRCA1-related solitary peritoneal carcinoma during breast screening--A case report.

BACKGROUND: The reported cumulative risk of developing primary peritoneal carcinoma (PPC) one to 20 years after prophylactic bilateral oophorectomy is 3.5% to 4.3%. Virtually all reported cases have been stage III or IV. CASE: During MRI screening of the breasts, an incidental mass on the surface of the liver was identified in a 56-year-old BRCA1 mutation carrier who had undergone prophylactic bilateral salpingo-oophorectomy several years previously with no evidence of malignancy. After four cycles of chemotherapy a localized, grade 3 serous papillary adenocarcinoma was resected followed by further chemotherapy and radiation. She remains disease-free 3 years post-treatment. CONCLUSION: The literature on PPC after prophylactic oophorectomy is reviewed. To the best of our knowledge, this is the first description of an apparently localized case of BRCA related PPC outside the pelvis.

Breast cancers detected with imaging screening in the BRCA population: emphasis on MR imaging with histopathologic correlation.

The benefit of screening with breast magnetic resonance (MR) imaging for certain patient populations at high risk for breast cancer, most notably patients with a genetic mutation in the BRCA1 or BRCA2 gene, has been established in numerous studies and is now becoming part of routine clinical practice. Despite the lower sensitivity of mammography compared with that of MR imaging, the former remains the standard of care for screening any patient population. In the BRCA1 and BRCA2 populations, the inferior sensitivity and specificity of ultrasonography (US) limit its role as a screening tool, but US remains a vital diagnostic tool because of its ability to provide guidance for biopsy of many suspicious lesions detected with MR imaging. Important features of a screening program with breast MR imaging include the following: optimization of the MR imaging technique, an awareness of the imaging features of invasive and noninvasive breast cancers detected with MR imaging, an understanding of the limitations of the various imaging modalities in both the initial screening and subsequent diagnostic work-up evaluations, and the requirement for MR imaging-guided biopsy.

MR imaging-guided breast localization system with medial or lateral access.

PURPOSE: To evaluate the degree of error of the authors' magnetic resonance (MR) imaging-guided needle localization system for biopsy of suspicious lesions visualized only with MR imaging, by using both prospectively recorded and retrospectively reviewed data, including MR imaging lesion coordinates as the reference standard, and to determine whether any lesion or breast characteristics affect this error. MATERIALS AND METHODS: Institutional review board approval, along with informed consent, was obtained as directed by the board. In 31 patients (age range, 34-64 years; mean age, 54.5 years), 38 wires were placed for 35 lesions by means of an MR-guided needle localization system with medial or lateral access and computer software assistance for needle placement calculation. Needle and wire placement error measurements were calculated before and after necessary placement correction, accounting for tissue shift in the z plane. The error was statistically correlated with MR imaging lesion variables, breast density, and histopathologic findings by means of univariate and multivariate linear regression analyses or two-tailed paired t test. Procedure times and the frequency of medial or lateral approaches were recorded. RESULTS: Eleven of 35 localizations (31%) were medial, and 24 of 35 (69%) were lateral. The mean total magnet time was 61.6 minutes, and the mean needle deployment time was 9 minutes (range, 4-17 minutes). Sixteen of 35 lesions (46%) were malignant (seven ductal carcinoma in situ, six invasive ductal, two invasive lobular, and one lymphoma). The mean uncorrected needle placement error was 1.3 mm (range, 0-6 mm) for the x plane, 2.4 mm (range, 0-6.5 mm) for the y plane, and 5.6 mm (range, 0-15.6 mm) for the z plane. Fourteen of 38 needles (37%) required repositioning for z-plane error. The corrected z-plane error improved to 3.2 mm (range, 0-10.0 mm). Factors that significantly increased the uncorrected error included tissue shift in the z plane (R = 0.7), small lesion size (R = -0.59), and fatty breast density (P = .029). CONCLUSION: The authors' system is accurate for performing MR-guided needle localizations for both medial and lateral approaches. Factors that increased the uncorrected needle placement error included small lesion size, fatty breast density, and tissue shift in the z plane.

Surveillance of BRCA1 and BRCA2 mutation carriers with magnetic resonance imaging, ultrasound, mammography, and clinical breast examination.

CONTEXT: Current recommendations for women who have a BRCA1 or BRCA2 mutation are to undergo breast surveillance from age 25 years onward with mammography annually and clinical breast examination (CBE) every 6 months; however, many tumors are detected at a relatively advanced stage. Magnetic resonance imaging (MRI) and ultrasound may improve the ability to detect breast cancer at an early stage. OBJECTIVE: To compare the sensitivity and specificity of 4 methods of breast cancer surveillance (mammography, ultrasound, MRI, and CBE) in women with hereditary susceptibility to breast cancer due to a BRCA1 or BRCA2 mutation. DESIGN, SETTING, AND PARTICIPANTS: A surveillance study of 236 Canadian women aged 25 to 65 years with BRCA1 or BRCA2 mutations who underwent 1 to 3 annual screening examinations, consisting of MRI, mammography, and ultrasound at a single tertiary care teaching hospital between November 3, 1997, and March 31, 2003. On the day of imaging and at 6-month intervals, CBE was performed. MAIN OUTCOME MEASURES: Sensitivity and specificity of each of the 4 surveillance modalities, and sensitivity of all 4 screening modalities vs mammography and CBE. RESULTS: Each imaging modality was read independently by a radiologist and scored on a 5-point Breast Imaging Reporting and Data System scale. All lesions with a score of 4 or 5 (suspicious or highly suspicious for malignancy) were biopsied. There were 22 cancers detected (16 invasive and 6 ductal carcinoma in situ). Of these, 17 (77%) were detected by MRI vs 8 (36%) by mammography, 7 (33%) by ultrasound, and 2 (9.1%) by CBE. The sensitivity and specificity (based on biopsy rates) were 77% and 95.4% for MRI, 36% and 99.8% for mammography, 33% and 96% for ultrasound, and 9.1% and 99.3% for CBE, respectively. There was 1 interval cancer. All 4 screening modalities combined had a sensitivity of 95% vs 45% for mammography and CBE combined. CONCLUSIONS: In BRCA1 and BRCA2 mutation carriers, MRI is more sensitive for detecting breast cancers than mammography, ultrasound, or CBE alone. Whether surveillance regimens that include MRI will reduce mortality from breast cancer in high-risk women requires further investigation.

Venous vascular malformations in pediatric patients: comparison of results of alcohol sclerotherapy with proposed MR imaging classification.

PURPOSE: To compare the clinical results of percutaneous sclerotherapy of venous vascular malformations (VVMs) with the authors' proposed magnetic resonance (MR) imaging classification. MATERIALS AND METHODS: MR findings and clinical results of percutaneous alcohol sclerotherapy in 59 pediatric patients with VVMs were retrospectively reviewed. Before treatment, lesions were graded with MR imaging on the basis of margins and size, respectively: grade 1, well defined, less than or equal to 5 cm; grade 2A, well defined, greater than 5 cm; grade 2B, ill defined, less than or equal to 5 cm; and grade 3, ill defined, greater than 5 cm. Regression models were used to test trends in therapy across the MR classification grades, including the repeat sclerotherapies, volumes of ethanol and metrizamide administered for each lesion, and number of access sites. Clinical response to sclerotherapy, which was evaluated with consensus by a multidisciplinary team, was graded as poor, good, or excellent. Association between MR imaging grade and clinical assessment was tested with the Fisher exact test. RESULTS: There were 14 grade 1 lesions, nine grade 2A, 15 grade 2B, and 21 grade 3. Twenty-four patients had a poor response to sclerotherapy; 19, good; and 16, excellent. Ten of 14 (71%) grade 1 lesions had an excellent response; none, a poor response. Twelve of 21 (57%) grade 3 lesions had a poor response; none, an excellent result. Grade 2 lesions were relatively equally distributed among the three categories, with the exception of nine of 15 (60%) grade 2B lesions that had a poor response (P <.001). There was a trend with increasing lesion grade for increasing numbers of sclerotherapy sessions, volumes of ethanol and metrizamide for each lesion, and numbers of access sites. CONCLUSION: There is a strong association between this proposed MR imaging classification and the results of percutaneous sclerotherapy.