Adjuvant radiotherapy for primary breast cancer in BRCA1 and BRCA2 mutation carriers and risk of contralateral breast cancer with special attention to patients irradiated at younger age

The purpose of this study was to estimate the influence of adjuvant radiotherapy for primary breast cancer (BC) on the risk of contralateral BC (CBC) in BRCA1 or BRCA2(BRCA1/2) mutation carriers, with special attention to patients irradiated at age younger than 40 years. Additionally, tendencies in locoregional treatments and rates of contralateral risk-reducing mastectomy over time were explored. In this retrospective cohort study, 691 BRCA1/2-associated BC patients treated between 1980 and 2013 were followed from diagnosis until CBC or censoring event including ipsilateral BC recurrence, distant metastasis, contralateral risk-reducing mastectomy, other invasive cancer diagnosis, death, or loss to follow up. Hazard ratios (HR) for CBC associated with radiotherapy were estimated using Cox regression. Median follow-up time was 8.6 years [range 0.3–34.3 years]. No association between radiotherapy for primary BC and risk of CBC was found, neither in the total population (HR 0.82, 95 % CI 0.45–1.49) nor in the subgroup of patients younger than 40 years at primary diagnosis (HR 1.36, 95 % CI 0.60–3.09). During follow-up, the number of patients at risk decreased substantially since a large proportion of patients were censored after contralateral risk-reducing mastectomy or BC recurrence. Over the years, increasing preference for mastectomy without radiotherapy compared to breast-conserving surgery with radiotherapy was found ranging from less than 30 % in 1995 to almost 50 % after 2010. The rate of contralateral risk-reducing mastectomy increased over the years from less than 40 % in 1995 to more than 60 % after 2010. In this cohort of BRCA1/2-associated BC patients, no association between radiotherapy for primary BC and risk of CBC was observed in the total group, nor in the patients irradiated before the age of 40 years. The number of patients at risk after 10 and 15 years of follow-up, however, was too small to definitively exclude harmful effects of adjuvant radiotherapy

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

Disproportionate Intrauterine Growth Intervention Trial At Term: DIGITAT

Contains fulltext : 65628.pdf ( ) (Open Access)BACKGROUND: Around 80% of intrauterine growth restricted (IUGR) infants are born at term. They have an increase in perinatal mortality and morbidity including behavioral problems, minor developmental delay and spastic cerebral palsy. Management is controversial, in particular the decision whether to induce labour or await spontaneous delivery with strict fetal and maternal surveillance. We propose a randomised trial to compare effectiveness, costs and maternal quality of life for induction of labour versus expectant management in women with a suspected IUGR fetus at term. METHODS/DESIGN: The proposed trial is a multi-centre randomised study in pregnant women who are suspected on clinical grounds of having an IUGR child at a gestational age between 36+0 and 41+0 weeks. After informed consent women will be randomly allocated to either induction of labour or expectant management with maternal and fetal monitoring. Randomisation will be web-based. The primary outcome measure will be a composite neonatal morbidity and mortality. Secondary outcomes will be severe maternal morbidity, maternal quality of life and costs. Moreover, we aim to assess neurodevelopmental and neurobehavioral outcome at two years as assessed by a postal enquiry (Child Behavioral Check List-CBCL and Ages and Stages Questionnaire-ASQ). Analysis will be by intention to treat. Quality of life analysis and a preference study will also be performed in the same study population. Health technology assessment with an economic analysis is part of this so called Digitat trial (Disproportionate Intrauterine Growth Intervention Trial At Term). The study aims to include 325 patients per arm. DISCUSSION: This trial will provide evidence for which strategy is superior in terms of neonatal and maternal morbidity and mortality, costs and maternal quality of life aspects. This will be the first randomised trial for IUGR at term. TRIAL REGISTRATION: Dutch Trial Register and ISRCTN-Register: ISRCTN10363217