Exposure to diagnostic radiation and risk of breast cancer among carriers of BRCA1/2 mutations: Retrospective cohort study (GENE-RAD-RISK)

Netherlands Cancer Institute, Department of Epidemiology and Biostatistics, Plesmanlaan 121, 1066 CX Amsterdam, Netherlands.
BMJ (online) (Impact Factor: 17.45). 09/2012; 345(sep06 2):e5660. DOI: 10.1136/bmj.e5660
Source: PubMed


Objective To estimate the risk of breast cancer associated with diagnostic radiation in carriers of BRCA1/2 mutations.
Design Retrospective cohort study (GENE-RAD-RISK).
Setting Three nationwide studies (GENEPSO, EMBRACE, HEBON) in France, United Kingdom, and the Netherlands,
Participants 1993 female carriers of BRCA1/2 mutations recruited in 2006-09.
Main outcome measure Risk of breast cancer estimated with a weighted Cox proportional hazards model with a time dependent individually estimated cumulative breast dose, based on nominal estimates of organ dose and frequency of self reported diagnostic procedures. To correct for potential survival bias, the analysis excluded carriers who were diagnosed more than five years before completion of the study questionnaire.
Results In carriers of BRCA1/2 mutations any exposure to diagnostic radiation before the age of 30 was associated with an increased risk of breast cancer (hazard ratio 1.90, 95% confidence interval 1.20 to 3.00), with a dose-response pattern. The risks by quarter of estimated cumulative dose <0.0020 Gy, ≥0.0020-0.0065 Gy, ≥0.0066-0.0173 Gy, and ≥0.0174 Gy were 1.63 (0.96 to 2.77), 1.78 (0.88 to 3.58), 1.75 (0.72 to 4.25), and 3.84 (1.67 to 8.79), respectively. Analyses on the different types of diagnostic procedures showed a pattern of increasing risk with increasing number of radiographs before age 20 and before age 30 compared with no exposure. A history of mammography before age 30 was also associated with an increased risk of breast cancer (hazard ratio 1.43, 0.85 to 2.40). Sensitivity analysis showed that this finding was not caused by confounding by indication of family history.
Conclusion In this large European study among carriers of BRCA1/2 mutations, exposure to diagnostic radiation before age 30 was associated with an increased risk of breast cancer at dose levels considerably lower than those at which increases have been found in other cohorts exposed to radiation. The results of this study support the use of non-ionising radiation imaging techniques (such as magnetic resonance imaging) as the main tool for surveillance in young women with BRCA1/2 mutations.

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Available from: Dafydd Gareth Evans
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    • "If a new “big picture” approach to breast cancer is to emerge, it is necessary to step back from the gene-dominated approaches to causation and examine what might cause this cancer at the gross level and what issues there are in establishing preventative or delaying techniques rather than aggressive treatment approaches. There are well known causes of breast cancer, such as the “Western diet” and the fact that Asian women have a reduced incidence until they come to reside in the West,5–7 smoking,8–10 and radiation exposure.11–13 There is also an ongoing controversy concerning the old idea dating back to 1943 that breast cancer may be caused by a handful of known oncogenic viruses.14,15 "
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    ABSTRACT: This discussion paper seeks to provoke thoughts about cancer research in general, and why breast cancer in particular is not yet "curable". It asks the question - are we looking at the disease in the right way? Should we regard cancer as a progressive state, which is part of aging? Should we tailor treatment to "reset" the system or slow progression rather than try using toxic and aggressive therapy to kill every cancer cell (and sometimes also the patient)? The thesis is presented that we need to revisit our fundamental beliefs about the disease and then ask why we cling to beliefs that clearly are no longer valid. The paper also questions the role of ethics boards in hampering research and discusses the concept that breast cancer is an industry with vested interests involving profiteering by preventive, diagnostic, and therapeutic players. Finally, the paper suggests some ways forward based on emerging concepts in system biology and epigenetics.
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    • "Women at high risk of breast and ovarian cancers are usually more susceptible to radiation-induced cancer because most of tumor suppressor genes implicated in breast cancer susceptibility are also implicated in the radio-induced DNA damage repair and signaling such as BRCA1/2, TP53 and ATM[45,46]. The results of a European cohort study associates diagnostic radiation before the age of 30 with an increased risk of breast cancer among BRCA1/2 mutation carriers [47]. Unfortunately, this is the group of women most exposed to low energy radiation, since they are subject to annual prophylactic screening by the age of 30–35, while in the rest of population, mammography is recommended at age 40 [48]. "
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    ABSTRACT: MicroRNAs are non-coding RNAs involved in the regulation of gene expression including DNA damage responses. Low doses of low energy X-ray radiation, similar to those used in mammographic exams, has been described to be genotoxic. In the present work we investigated the expression of miR-34a; a well described p53-regulated miRNA implicated in cell responses to X-ray irradiation at low doses. Non-cancerous breast cell line MCF-10A and cancerous T-47D and MCF-7 cell lines were submitted to a low-energy X-ray irradiation (ranging from 28--30 Kv) using a dose of 5 Gy. The expression level of miR-34a, let-7a and miR-21 was assessed by qRT-PCR at 4 and 24 hours post-irradiation. DNA damage was then measured by comet assay and micronuclei estimation in MCF-10A and MCF-7 cell lines, where an increase of miR-34a levels could be observed after irradiation. The rate of apoptotic cells was estimated by nuclear staining and fluorescence microscopy. These experiments were also performed at low doses (3; 12 and 48 mGy) in MCF-10A and MCF-7 cell lines. We have observed an increase in miR-34a expression 4 hours post-irradiation at 5 Gy in MCF-10A and MCF-7 cell lines while its level did not change in T-47D, a breast cancer cell line bearing non-functional p53. At low doses, miR-34a was up-regulated in non-tumoral MCF-10A to a higher extent as compared to MCF-7. MiR-34a levels decreased 24 hours post-irradiation. We have also observed DNA damage and apoptosis at low-energy X-ray irradiation at low doses and the high dose in MCF-10A and MCF-7 4 and 24 hours post-irradiation relative to the mock control. Low energy X-ray is able to promote DNA strand breaks and miR-34a might be involved in cell responses to low energy X-ray DNA damage. MiR-34a expression correlates with X-ray dose, time after irradiation and cell type. The present study reinforces the need of investigating consequences of low dose X-ray irradiation of breast cells.
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    • "It has an increased risk of false-positive results at young age (Armstrong et al, 2007), which may cause distress and unnecessary biopsies, including surgical biopsy. It also gives an additional risk of radiation-induced tumours, which is particularly relevant in younger women (Preston et al, 2002; BEIR 7, 2006) and in those with cancer susceptibility genes (Jansen-van der Weide et al, 2010; Pijpe A et al, 2012). "
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