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MRI Characteristics of BRCA – Associated Breast Cancers A. K. Kelekar, S. Mukherjee, C. Mitri, F. Khan, W. Ducaine, L. Dohany, D. Zakalik Abstract Background: Magnetic Resonance Imaging (MRI) is the preferred imaging modality for screening and diagnosis of breast cancer in BRCA-1 and BRCA-2 mutation carriers. However, there is limited data on the radiographic features of BRCA1/2-positive breast cancers on MRI. This study evaluates the MRI characteristics of BRCA1/2 -related breast cancers. Methods: All female BRCA mutation carriers with a biopsy proven breast cancer, imaged with MRI for screening or preoperative evaluation at William Beaumont hospital between April 2002 until January 2011, were included in the study. A total of 47 mutation carriers were identified. All MRI examinations were retrospectively evaluated by an independent radiologist for the following characteristics: shape, margin, enhancement, T2 intratumoral intensity. Results: A majority of BRCA- associated breast tumors were morphologically irregular, T2 hypointense lesions on MRI with heterogeneous enhancement. No statistically significant differences were noted among the BRCA-1 and -2 mutations carriers. Conclusions: Previous studies have reported that BRCA-associated breast cancers demonstrate morphological characteristics that resemble benign tumors i.e. round shape and smooth margins. Our study however, showed features more typical of malignant lesions i.e. irregular shape and margin. Low T2 intratumoral intensity tumors were commonly seen in our cohort, although BRCA-1 patients often develop triple negative tumors which typically are high intensity. These differences may be explained by small sample size or population differences. Future research is needed with larger patient cohorts to elucidate the unique MRI characteristics of BRCA- related cancers. MRI Characteristic SHAPE Round Lobulated Irregular BRCA-1 3 8 19 BRCA-2 4 3 12 BRCA1+2 7 (14.3%) 11 (22.4%) 31 (63.3%) MARGIN Smooth Irregular 3 26 3 17 6 (12.2%) 43 (87.8%) 5 19 5 2 13 5 7 (14.3%) 32 (65.3%) 10 (20.4%) ENHANCEMENT Homogenous Heterogeneous Rim T2 INTRATUMORAL INTENSITY Low Equal High 25 4 1 21 0 2 46 (86.8%) 4 (7.6%) 3 (5.7%) • Several studies have demonstrated that Magnetic Resonance Imaging (MRI) is the preferred imaging modality for screening and diagnosis of breast cancer in BRCA-1 and BRCA-2 mutation carriers.(3-5) • These studies, comparing the various imaging modalities in BRCA mutation carriers, show contrast enhanced MRI to be more sensitive than mammography, breast ultrasound or clinical breast exam. However the specificity of MRI is lower than mammography, breast ultrasound and clinical breast examination respectively. (3-5) Results • The following terminology was used for describing the features of breast cancers on MRI: - Mass shape: Round or oval, lobulated or irregular - Mass margin; Smooth (if well defined) or irregular (if ill defined) - On unenhanced T2 weighted fat suppressed images, the lesions were described as low, equal or high intensity in comparison to normal breast tissue. - Contrast enhanced T1-weighted images were described based on patterns of early enhancement as homogenous, heterogeneous or rim enhancement. • Dynamic changes of enhancement were not analyzed. • Use of MRI for surveillance can result in the diagnosis of familial cancers at an earlier stage.(3) Hence, current guidelines recommend use of MRI for surveillance in women with a high risk of developing breast cancer.(6) • Two cases of non mass enhancement were identified which could not be described with the above characteristics, hence they were excluded for the study. • Review of literature yields few studies exploring the radiographic features of BRCA associated breast cancers on MRI. Table 1: MRI characteristics Methods • 276 females diagnosed with BRCA- associated breast cancer at the Cancer Genetics Program at William Beaumont Hospital between April 2002 and January 2011 were included in the study. • On review of the electronic medical records, 47 patients with 49 tumors were identified who had biopsy-proven breast cancer and underwent preoperative MRI. • Bilateral breast MRI’s were performed using an MRI machine with the following specifications: - Magnetic field strength= 1.5 T and 3 T of the older and newer machine respectively. - Homogenous magnetic field - Bilateral imaging • Two patients had locally recurrent breast cancers and each lesion was separately analyzed. BRCA-1 BRCA-2 p (Chi square) for BRCA-1 vs. BRCA- 2 Round 3 4 Lobulated Irregular 8 19 3 12 Total=49 0.45 (not significant) Smooth 3 3 Irregular 26 17 Total=49 MRI Characteristic SHAPE MARGIN ENHANCEMENT Homogenous 5 2 Heterogeneous Rim 19 5 13 5 Total=49 T2 INTRATUMORAL INTENSITY Low 25 21 Equal High 4 1 0 2 Total=50 (Extra case of linear enhancement) - Contrast-enhanced imaging with gadolinium chelate - Unenhanced T2-weighted fat-suppressed imaging - Assessment of lesion morphology adhering to the following criteria: Small pixel size (< or equal to 1 mm), thin section thickness (< or equal to 3 mm) • Lesion enhancement kinetics were not evaluated, as MRI’s done prior to June 2010 did not consistently perform or report the findings. Total BRCA positive patients BRCA-1 BRCA-2 Total Tumors analyzed Mean age of patient Introduction Pure DCIS(Ductal carcinoma insitu) DCIS+ invasive cancer Invasive cancer • The breast cancer susceptibility genes, BRCA-1 and -2, are believed to be responsible for majority of hereditary breast/ovarian cancer.(1) • Differences in MRI findings between BRCA-1 and -2 associated cancers was evaluated for statistical significance (p<0.05) using the Chi square test (with graph pad prism software). Average size of tumor • The protocol for this retrospective study was approved by the Human Investigation Committee of the William Beaumont Hospital. 0.53 (not significant) 0.47 (not significant) 0.09 (not significant) Total (BRCA1+2) percentage 7 14.3 11 31 22.4 63.3 6 12.2 43 87.8 7 14.3 32 10 65.3 20.4 46 86.8 4 3 7.6 5.7 • A majority of BRCA- associated breast tumors had irregular shape, irregular (ill defined) borders and appeared as T2 hypointense lesions on MRI with heterogeneous enhancement. • No statistically significant differences were noted among the BRCA-1 and -2 mutations carriers with respect to the above mentioned features. • A significantly high percentage (61.9%) of DCIS either alone or in combination with invasive cancer was noted in our study cohort. • Triple negative tumors occurred in 69% of BRCA-1 patients and 33.3% of BRCA-2 patients. Figure 1. The most common MRI finding in our patients: Irregular shape and margin with heterogeneous enhancement. Conclusions and Discussion • The majority of BRCA related tumors had irregular shape and margin, features that are often associated with sporadic malignant breast cancers. • This was in contrast to previous studies which have described BRCA-associated breast cancers to have features closely resembling benign tumors such as rounded lesions with sharp, well defined margins.(7) • A possible explanation for this observation could be a higher proportion of DCIS tumors (61.9%) compared to previous reports (37%), leading to a characteristic radiographic appearance.(8) • Most cancers in our study demonstrated heterogenous intratumoral enhancement. Prior studies have demonstrated both rim enhancement and heterogenous enhancement with equal frequency.(7)(9) • MRI appearance of tumors in this study was predominantly low intensity on T2 weighted images. Previous studies have reported both low and high T2 weighted signal intensity in BRCA associated breast cancers.(7)(9)(10) • Despite having a higher frequency of triple negative breast tumors in our cohort, our patients did not demonstrate the previously described characteristics of triple negative tumor i.,e smooth margins, ring enhancement and high intratumoral intensity. • The differences between our study findings and prior reports may be explained by small size or population differences. Figure 2. The most common MRI finding previously described in BRCA patients and encountered less frequently in our cohort: Round shape, smooth margin. This lesion shows homogeneous enhancement. • MRI findings of BRCA related breast cancers demonstrate variable characteristics. Hence any abnormality detected on MRI should be viewed with suspicion in these high-risk patients and warrant biopsy for histopathologic confirmation • One of the limitations of this study was the inability to assess dynamic enhancement kinetics. Prior research has demonstrated similar enhancement kinetics i.e. type 3 curve or washout pattern, between BRCA mutation carriers and non carriers, although this was not able to be evaluated in the current study.(7) • Future research is needed to further elucidate the unique MRI characteristics of BRCArelated cancers. References Table 2: Patient characteristics • The selected MRI images were reviewed by an independent radiologist blinded to the BRCA mutation status of the breast cancer patients. • For BRCA-1 mutation carriers the risk of developing breast cancer by age 70 years is 65% (95% confidence interval 44%-78%). The risk for BRCA2- mutation carriers is 45% (31%-56%). The risk is estimated to be higher if the index breast cancer case was diagnosed at an age less than 35 years.(2) Beaumont Hospital, Royal Oak, MI 47 29 18 49 44.7 years 3 26 18 1.6 cm BRE Grade 1 BRE Grade 2 BRE Grade 3 3 18 24 Triple negative (total) Triple negative BRCA-1 Triple negative BRCA-2 Lymph node involvement Tumor Necrosis 26 20 6 18 7 Figure 3. Irregular shape and margin with rim enhancement: Typical features of sporadic malignant breast cancer. 1. Szabo CI, King MC. Population genetics of BRCA-1 and BRCA-2. Am J Hum Genet 1997; 60(5):1013–1020. 2. Antoniou A, Pharoah PD, Narod S, et al. Average risks of breast and ovarian cancer associated with BRCA-1 or BRCA-2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 2003; 72(5):1117–1130. 3. Kuhl CK, Schrading S, Leutner CC, et al. Mammography, breast ultrasound, and magnetic resonance imaging for surveillance of women at high familial risk for breast cancer. J Clin Oncol 2005; 23(33):8469–8476. 4. Warner E, Plewes DB, Hill KA, et al. Screening with magnetic resonance imaging and mammography of a UK population at high familial risk of breast cancer: a prospective multicentre cohort study (MARIBS). JAMA 2004;292(11):1317–1325. 5. Kriege M, Brekelmans CT, Boetes C, et al. Efficacy of MRI and mammography for breast-cancer screening in women with a familial or genetic predisposition. N Engl J Med 2004;351(5):427–437. 6. Sardanelli F, Podo F, D’Agnolo G, Verdecchia A, Santaquilani M, Musumeci R, Trecate G, Manoukian S, Morassut S, De Giacomi C, Federico M, Cortesi L, Corcione S, Cirillo S, Marra V, Cilotti A, Di Maggio C, Fausto A, Preda L, Zuiani C Contegiacomo A, Orlacchio A, Calabrese M, Bonomo L, Di Cesare E, Tonutti M, Panizza P, Del Maschio A (2007). Multicenter comparative multimodality surveillance of women at genetic-familial high risk for breastcancer (HIBCRIT study): interim results. Radiology 242:698–715 7. J. Veltman, R. Mann, T. Kok, I. M. Obdeijn, N. Hoogerbrugge, J. G. Blickman and C. Boetes. Breast tumor characteristics of BRCA-1 and BRCA-2 gene mutation carriers on MRI . Eur Radiol (2008) 18: 931–938 8. Hwang ES, McLennan JL, Moore DH, Crawford BB, Ziegler JL. Ductal carcinoma in situ in BRCA- mutation carriers. J Clin Oncol. 2007 Feb 20;25(6):642-7. Epub 2007 Jan 8 9. Masayuki Onishi, Akira Furukawa, Masashi Takahashi, Kiyoshi Murata. A wide variety of dynamic contrast-enhanced MR appearances of breast cancer: Pathologic correlation study. European Journal of Radiology 65 (2008) 286–292 10. Giovanna Trecate, Siranuosh Manoukian, Laura Suman, Daniele Vergnaghi, Monica Marchesini, Roberto Agresti, Cristina Ferraris, Bernard Peissel, Davide Scaramuzza1, and Silvana Bergonzi. Unit of Diagnostic Radiology, Department of Experimental Oncology-Medical Genetics. Is there a specific magnetic resonance phenotype characteristic of hereditary breast cancer? Tumori, 96: 363-384, 2010 11. Atchley DP, Albarracin CT, Lopez A, Valero V, Amos CI, Gonzalez-Angulo AM, Hortobagyi GN, Arun BK. Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer. J Clin Oncol. 2008 Sep 10;26(26):4282-8. 12. Takayoshi Uematsu, MD, PhD, Masako Kasami,, MD, PhD and Sachiko Yuen, MD, PhD. Triple-Negative Breast Cancer: Correlation between MR Imaging and Pathologic Findings. March 2009 Radiology, 250, 638-647. P6118_0611