Increased chromosomal radiosensitivity in asymptomatic carriers of a heterozygous BRCA1 mutation

Background: Breast cancer risk increases drastically in individuals carrying a germline BRCA1 mutation. The exposure to ionizing radiation for diagnostic or therapeutic purposes of BRCA1 mutation carriers is counterintuitive, since BRCA1 is active in the DNA damage response pathway. The aim of this study was to investigate whether healthy BRCA1 mutations carriers demonstrate an increased radiosensitivity compared with healthy individuals. Methods: We defined a novel radiosensitivity indicator (RIND) based on two endpoints measured by the G2 micronucleus assay, reflecting defects in DNA repair and G2 arrest capacity after exposure to doses of 2 or 4 Gy. We investigated if a correlation between the RIND score and nonsense-mediated decay (NMD) could be established. Results: We found significantly increased radiosensitivity in the cohort of healthy BRCA1 mutation carriers compared with healthy controls. In addition, our analysis showed a significantly different distribution over the RIND scores (p = 0.034, Fisher’s exact test) for healthy BRCA1 mutation carriers compared with non-carriers: 72 % of mutation carriers showed a radiosensitive phenotype (RIND score 1–4), whereas 72 % of the healthy volunteers showed no radiosensitivity (RIND score 0). Furthermore, 28 % of BRCA1 mutation carriers had a RIND score of 3 or 4 (not observed in control subjects). The radiosensitive phenotype was similar for relatives within several families, but not for unrelated individuals carrying the same mutation. The median RIND score was higher in patients with a mutation leading to a premature termination codon (PTC) located in the central part of the gene than in patients with a germline mutation in the 5′ end of the gene. Conclusions: We show that BRCA1 mutations are associated with a radiosensitive phenotype related to a compromised DNA repair and G2 arrest capacity after exposure to either 2 or 4 Gy. Our study confirms that haploinsufficiency is the mechanism involved in radiosensitivity in patients with a PTC allele, but it suggests that further research is needed to evaluate alternative mechanisms for mutations not subjected to NMD

Breast Fine-Needle Aspiration Cytology Performance in the High-Risk Screening Population

BACKGROUNDThe diagnosis of breast lesions is usually confirmed by fine-needle aspiration cytology (FNAC) or histological biopsy. Although there is increasing literature regarding the advantages and limitations of both modalities, there is no literature regarding the accuracy of these modalities for diagnosing breast lesions in high-risk patients, who usually have lesions detected by screening. The objective of the current study was to evaluate diagnostic performance indices of FNAC in breast cancer susceptibility gene (BRCA) mutation carriers. METHODSBRCA1/BRCA2 mutation carriers who underwent FNAC were selected from the database of the Rotterdam Family Cancer Clinic. FNAC accuracy parameters were calculated by taking the outcome of a subsequent histological diagnosis or clinical follow-up as reference standard. RESULTSIn total, 320 FNACs were obtained, and FNAC examination was followed by histological examination in 150 patients. The rate of insufficient material was 25.6%. Sensitivity was 92.3%, specificity 96.3%. The false-positive rate was 3.7%, the false-negative rate was 7.7%, and accuracy was 94.7%. A substantial proportion of patients (35%) with malignant FNAC results underwent histological biopsy upfront surgical resection. Small lesion size (1 cm) and nonpalpability of the breast lesion were a CONCLUSIONSThere is a role for FNAC in diagnosing breast lesions of BRCA1/BRCA2 mutation carriers, ie, to confirm a radiological (probably) benign lesion. However, despite the high overall sensitivity of FNAC, the authors recommend histological biopsy as the preferred diagnostic method for high-risk patients who have small or nonpalpable lesions. Cancer (Cancer Cytopathol) 2013;121:561-567. (c) 2013 American Cancer Society. There is a role for fine-needle aspiration cytology in diagnosing breast lesions from BRCA1/BRCA2 mutation carriers, ie, to confirm a radiological (probably) benign lesion. However, despite the high overall sensitivity of fine-needle aspiration cytology, the authors recommend histological biopsy as the preferred diagnostic method in high-risk patients with small or nonpalpable lesions

An ultrasound cylindrical phased array for deep heating in the breast:theoretical design using heterogeneous models

\u3cp\u3eThe objective of this theoretical study is to design an ultrasound (US) cylindrical phased array that can be used for hyperthermia (40-44 degrees C) treatment of tumours in the intact breast. Simultaneously, we characterize the influence of acoustic and thermal heterogeneities on the specific absorption rate (SAR) and temperature patterns to determine the necessity of using heterogeneous models for a US applicator design and treatment planning. Cylindrical configurations of monopole transducers are studied on their ability to generate interference patterns that can be steered electronically to the location of the target region. Hereto, design parameters such as frequency, number of transducers per ring, ring distance and number of rings are optimized to obtain a small primary focus, while suppressing secondary foci. The models account for local heterogeneities in both acoustic (wave velocity and absorption) and thermal (blood perfusion rate, heat capacity and conductivity) tissue properties. We used breast models with a central tumour (30x20x38 mm3) and an artificial thorax tumour (sphere with a radius of 25 mm) to test the design. Simulations predict that a US cylindrical phased array, consisting of six rings with 32 transducers per ring, a radius of 75 mm and 66 mm distance between the first and sixth transducer ring, operating at a frequency of 100 kHz, can be used to obtain 44 degrees C in the centre of tumours located anywhere in the intact breast. The dimensions of the volumes enclosed by the 41 degrees C iso-temperature are 19x19x21 mm3 and 21x21x32 mm3 for the central and the thorax tumours, respectively. It is demonstrated that acoustic and thermal heterogeneities do not disturb the SAR and temperature patterns.\u3c/p\u3

Differences between first and subsequent rounds of the MRISC breast cancer screening program for women with a familial or genetic predisposition

BACKGROUND. within the Dutch MRI Screening (MRISC) study, a Dutch multicenter screening study for hereditary breast cancer, the authors investigated whether previously reported increased diagnostic accuracy of magnetic resonance imaging (MRI) compared with mammography would be maintained during subsequent screening rounds. METHODS. From November 1999 to October 2003,1909 eligible women were included in the study. Screening parameters and tumor characteristics of different rounds were calculated and compared. The authors defined 3 different types of imaging screening rounds: first round in women never screened by imaging before, first round in women screened by imaging (mainly mammography) before, and subsequent rounds. RESULTS. The difference in sensitivity for invasive cancers between mammography and MRI was largest in the first round of women previously screened with mammography (20.0 vs. 93.3%; P =.003), but also in subsequent rounds, there was a significant difference in favor of MRI (29.4 vs. 76.5%; P =.02). The difference in false-positive rate between mammography and MRI was also largest in the first round of women previously screened with mammography (5.5 vs. 14.0%; P CONCLUSIONS. in subsequent rounds, a significantly higher sensitivity and better discriminating capacity of MRI compared with mammography was maintained, and a favorable tumor stage compared with age-matched symptomatic controls. As results of these subsequent screening rounds were most predictive for long-term effects, the authors expect that this screening program will contribute to a decrease of breast cancer mortality in these high-risk women