Proteomic signature for detection of high-grade ovarian cancer in germline BRCA mutation carriers.

No current screening methods for high-grade ovarian cancer (HGOC) guarantee effective early detection for high-risk women such as germline BRCA mutation carriers. Therefore, the standard-of-care remains risk-reducing salpingo-oophorectomy (RRSO) around age 40. Proximal liquid biopsy is a promising source of biomarkers, but sensitivity has not yet qualified for clinical implementation. We aimed to develop a proteomic assay based on proximal liquid biopsy, as a decision support tool for monitoring high-risk population. Ninety Israeli BRCA1 or BRCA2 mutation carriers were included in the training set (17 HGOC patients and 73 asymptomatic women), (BEDOCA trial; ClinicalTrials.gov Identifier: NCT03150121). The proteome of the microvesicle fraction of the samples was profiled by mass spectrometry and a classifier was developed using logistic regression. An independent cohort of 98 BRCA mutation carriers was used for validation. Safety information was collected for all women who opted for uterine lavage in a clinic setting. We present a 7-protein diagnostic signature, with AUC >0.97 and a negative predictive value (NPV) of 100% for detecting HGOC. The AUC of the biomarker in the independent validation set was >0.94 and the NPV >99%. The sampling procedure was clinically acceptable, with favorable pain scores and safety. We conclude that the acquisition of Müllerian tract proximal liquid biopsies in women at high-risk for HGOC and the application of the BRCA-specific diagnostic assay demonstrates high sensitivity, specificity, technical feasibility and safety. Similar classifier for an average-risk population is warranted.

Ductal Carcinoma In Situ (DCIS) Diagnosed by MRI-Guided Biopsy among BRCA1/BRCA2 Mutation Carriers.

Background: While BRCA1/BRCA2 pathogenic sequence variants (PSVs) clearly confer an increased risk for invasive breast cancer, the extent to which these mutant alleles increase DCIS risk is less clear. Objective: To assess the rate of detection over a 5-year period, and MRI imaging features of pure noncalcified DCIS in a cohort of Israeli BRCA1/BRCA2 PSV carriers attending a high-risk clinic from 2015 to 2020. Materials and Methods: All female BRCA1/BRCA2 PSV-carriers followed at the Meirav High-risk clinic from 2015 to 2020 were eligible if they underwent semiannual breast imaging (MRI/mammography) and MRI-guided biopsy-proven pure DCIS. Clinical data, pathology information, and imaging characteristics were retrieved from the computerized archiving system. Results: 18/121 (15.2%) participating BRCA1 PSV carriers and 8/81 (10.1%) BRCA2 PSV-carriers who underwent MRI-guided biopsy were diagnosed with DCIS. The median age of BRCA1 carriers and BRCA2 carriers was 49.8 years and 60.6 years, respectively (p = 0.55). Negative estrogen-receptor tumors were diagnosed in 13/18 (72%) BRCA1 and 2/8 (25%) BRCA2 PSV carriers (p < 0.05). Thirteen (13/18-72%) BRCA1 carriers had intermediate to high-grade or high-grade DCIS compared with 4/8 (50%) of BRCA2 carriers (p = 0.03). Over the 5-year study period, 29/1100 (2.6%) BRCA1/BRCA2 PSV carriers were diagnosed with DCIS seen on MRI only. Conclusion: MRI-detected noncalcified DCIS is more frequent in BRCA1 PSV carriers compared with BRCA2 carriers, unlike the BRCA2 predominance in mammography-detected calcified DCIS. BRCA1-related DCIS is diagnosed earlier, more likely to be estrogen receptor-negative and of higher grade compared with BRCA2-related DCIS. Future prospective studies should validate these results and assess the actual impact they might have on clinical management of BRCA PSV carriers.

Breast MRI during lactation: effects on tumor conspicuity using dynamic contrast-enhanced (DCE) in comparison with diffusion tensor imaging (DTI) parametric maps.

PURPOSE: To investigate the effect of lactation on breast cancer conspicuity on dynamic contrast-enhanced (DCE) MRI in comparison with diffusion tensor imaging (DTI) parametric maps. MATERIALS AND METHODS: Eleven lactating patients with 16 biopsy-confirmed pregnancy-associated breast cancer (PABC) lesions were prospectively evaluated by DCE and DTI on a 1.5-T MRI for pre-treatment evaluation. Additionally, DCE datasets of 16 non-lactating age-matched breast cancer patients were retrospectively reviewed, as control. Contrast-to-noise ratio (CNR) comprising two regions of interests of the normal parenchyma was used to assess the differences in the tumor conspicuity on DCE subtraction images between lactating and non-lactating patients, as well as in comparison against DTI parametric maps of λ1, λ2, λ3, mean diffusivity (MD), fractional anisotropy (FA), and maximal anisotropy index, λ1-λ3. RESULTS: CNR values of breast cancer on DCE MRI among lactating patients were reduced by 62% and 58% (p < 0.001) in comparison with those in non-lactating patients, when taking into account the normal contralateral parenchyma and an area of marked background parenchymal enhancement (BPE), respectively. Among the lactating patients, DTI parameters of λ1, λ2, λ3, MD, and λ1-λ3 were significantly decreased, and FA was significantly increased in PABC, relative to the normal lactating parenchyma ROIs. When compared against DCE in the lactating cohort, the CNR on λ1, λ2, λ3, and MD was significantly superior, providing up to 138% more tumor conspicuity, on average. CONCLUSION: Breast cancer conspicuity on DCE MRI is markedly reduced during lactation owing to the marked BPE. However, the additional application of DTI can improve the visualization and quantitative characterization of PABC, therefore possibly suggesting an additive value in the diagnostic workup of PABC. KEY POINTS: • Breast cancer conspicuity on DCE MRI has decreased by approximately 60% among lactating patients compared with non-lactating controls. • DTI-derived diffusion coefficients and the anisotropy indices of PABC lesions were significantly different than those of the normal lactating fibroglandular tissue. • Among lactating patients, breast cancer conspicuity on DTI-derived parametric maps provided up to 138% increase in contrast-to-noise ratio compared with DCE imaging.

Noncontrast Breast MRI During Pregnancy Using Diffusion Tensor Imaging: A Feasibility Study.

BACKGROUND: Pregnancy-associated breast cancer (PABC) is often a delayed diagnosis and contrast-enhanced MRI is contraindicated because gadolinium agents are known to cross the placenta. PURPOSE: To investigate the feasibility and clinical utility of noncontrast breast MRI using diffusion tensor imaging (DTI) in the diagnostic workup of PABC. STUDY TYPE: Prospective. POPULATION: Between November 2016 and January 2018, 25 pregnant participants (median gestational age: 17 weeks) were recruited from eight referral breast-care centers nationwide. Imaging indications included: newly-diagnosed PABC (n = 10, with 11 lesions), palpable mass/mastitis (n = 4), high-risk screening (n = 10), and monitoring neoadjuvant-chemotherapy response (n = 1). FIELD STRENGTH/SEQUENCE: 1.5T, T2 -weighted, and DTI sequences, prone position, with a scan duration of ∼12 minutes. ASSESSMENT: DTI parametric maps were generated and analyzed at pixel resolution, with reference to ultrasound (US) and pathology. STATISTICAL TESTS: Two-tailed Student's t-test was applied for evaluating differences between DTI parameters of PABC vs. healthy fibroglandular tissue. Pearson's correlation test was applied to measure the agreements between λ1-based longest tumor diameter, US, and pathology. RESULTS: All scans were technically completed and reached diagnostic quality, except one with notable motion artifacts due to positional discomfort, which was excluded. Nine out of 11 known PABC lesions and one newly-diagnosed lesion were visible on λ1, λ2, λ3, mean diffusivity (MD), and λ1-λ3 maps, with substantial parametric contrast compared with the apparently normal contralateral fibroglandular tissue (P < 0.001 for all). Two lesions of 0.7 cm were not depicted by the diffusivity maps. Tumor diameter measured on a thresholded λ1 map correlated well with US (r = 0.97) and pathology (r = 0.95). Malignancy was excluded by DTI parametric maps in scans of symptomatic and high-risk patients, in agreement with US follow-up, except for one false-positive case. DATA CONCLUSION: Noncontrast breast MRI is feasible and well-tolerated during pregnancy. Further studies with a larger and homogeneous cohort are required to validate DTI's additive diagnostic value, albeit this study suggests a potential adjunct role for this noninvasive approach in breast evaluation during pregnancy. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;49:508-517.

Pregnancy Associated Breast Cancer Among Israeli BRCA1/BRCA2 Carriers in a High-Risk Clinic.

RATIONALE AND OBJECTIVES: Female carriers of pathogenic sequence variants (PSVs) in the BRCA1 /BRCA2 (Breast Cancer gene - BRCA) genes are at a substantially high-risk for developing breast cancer (BC), hence are offered active surveillance scheme based on semiannual breast exam and imaging from age 25 years to facilitate BC early detection (mammography/breast ultrasound depending on the age, and MRI). However, there are not specific guidelines for screening in case of pregnancy or lactation. In the current study, we summarize the experience at the largest high-risk clinic in Israel. MATERIALS AND METHODS: Data of consecutive BRCA-PSV carriers undergoing surveillance as well as diagnostic ultrasound at the Meirav high-risk clinic from January 2014 to 2021 who were pregnant and/or breastfeeding at time of follow-up were identified. Relevant clinical data including results of breast exam, breast ultrasonography, biopsies and histological results were retrieved. Percentage of biopsies with malignancy, cancer detection rate and positive predictive values were calculated. Data is presented in descriptive statistics. RESULTS: A total of 263 BRCA-carriers were included. Of these, 593 breast-ultrasonograms were performed in 263 BRCA-carriers for 292 pregnancies and 409 breast-ultrasonograms for 175 breastfeeding carriers. Of 36 breast biopsies in 292 pregnancies, 4 (PPV = 11%) had BC diagnosed (high grade invasive). Of 175 breastfeeding women, 25 biopsies were performed and 2 (PPV = 8%) were high grade invasive BC. Five of 6 BC were diagnosed in BRCA1 carriers, and 4/6 were screen detected. The rate of pregnancy-associated breast cancer was 6/292 (2.05%). CONCLUSION: The overall detection rate of pregnancy-associated BC in BRCA-carriers is relatively low (2.05%), but still much higher than that in the general population. Two thirds of the BC were detected by screening. Therefore, despite the changes of the glandular breast tissue at time of pregnancy and breastfeeding, screening plays an important role in early detection. Ultrasound should be considered as a screening tool during this period of life of high-risk patients.

Abnormal Findings Detected by Multi-modality Breast Imaging and Biopsy Results in a High-risk Clinic.

BACKGROUND: High-risk BRCA mutation carriers are offered a surveillance scheme aimed at early detection of breast cancer. Although the efficacy of this scheme in breast cancer detection is well-established, the rate of breast cancer diagnosis of radiologically suspicious lesions and the effect of this screening scheme on breast cancer grade and stage are less well-defined. PATIENTS AND METHODS: Female BRCA1 and BRCA2 mutation carriers who were cancer-free at the beginning of follow-up at the Meirav High-risk Clinic, Sheba Medical Center, were eligible. Radiological imaging data (mammography, ultrasound, magnetic resonance imaging, Breast Imaging Reporting and Data System scores), and histopathologic data on breast biopsies were retrieved. RESULTS: Overall, 1055 women participated in the study; 760 (72%) were Ashkenazim, 661 (62.6%) were BRCA1 mutation carriers, the mean age at first visit was 44.1 ± 11.8 years, and there was a mean follow-up of 6.2 years. All participants underwent 6641 breast imaging tests: 2613 magnetic resonance imagings, 2662 breast ultrasounds, and 1366 mammograms. Overall, 295 biopsies were performed on 254 women: 82 (27%) biopsies on 79 women were diagnosed with breast cancer, including ductal carcinoma in situ: invasive breast cancer was diagnosed in 58 (70.7%), of whom 36 (62% of invasive cancer) were grade 3, and all but 10 were stage 1 to 2. Benign findings were noted in 213 biopsies performed on 175 women, with fibrocystic disease (n = 134; 62.9%) or fibroadenoma (n = 60; 28.16%) most commonly diagnosed. CONCLUSIONS: Adherence to a breast cancer surveillance scheme enables breast cancer detection at an early stage but at advanced grade. Most biopsies (72%) performed in this high-risk clinic are benign.