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Research Exposure to diagnostic radiation and risk of breast cancer among carriers of BRCA1/2 mutations: retrospective cohort study (GENE-RAD-RISK) BMJ 2012; 345 doi: 10.1136/bmj.e5660 (Published 6 September 2012) Cite this as: BMJ 2012;345:e5660 Breast cancer Epidemiologic studies Screening (oncology) Clinical diagnostic tests Radiology More topics Radiology (diagnostics) Fewer topics Article Related content Article metrics Anouk Pijpe, postdoctoral research fellow1, Nadine Andrieu, senior researcher234, Douglas F Easton, professor5, Ausrele Kesminiene, study coordinator6, Elisabeth Cardis, professor7, Catherine Noguès, oncogeneticist8, Marion Gauthier-Villars, oncogeneticist9, Christine Lasset, oncogeneticist10, Jean-Pierre Fricker, oncogeneticist11, Susan Peock, study coordinator5, Debra Frost, research assistant5, D Gareth Evans, professor12, Rosalind A Eeles, clinical cancer geneticist13, Joan Paterson, clinical geneticist14, Peggy Manders, postdoctoral research fellow115, Christi J van Asperen, clinical geneticist16, Margreet G E M Ausems, clinical geneticist17, Hanne Meijers-Heijboer, clinical geneticist18, Isabelle Thierry-Chef, researcher6, Michael Hauptmann, statistician1, David Goldgar, senior researcher19, Matti A Rookus, senior research fellow1, Flora E van Leeuwen, professor1 on behalf of GENEPSO, EMBRACE, and HEBON1Netherlands Cancer Institute, Department of Epidemiology and Biostatistics, Plesmanlaan 121, 1066 CX Amsterdam, Netherlands2Institut National de la Santé et de la Recherche Médicale, Unité U900, Paris 75248, France 3Institut Curie, Research Centre and Service of Biostatistics, Paris 75248 4Ecole des Mines de Paris, Paris Tech, Fontainebleau 77300, France 5Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge CB1 8RN, UK6International Agency for Research on Cancer, Section of Environment and Radiation, 69372 Lyon 08, France7Centre for Research in Environmental Epidemiology (CREAL), IMIM (Hospital del Mar Research Institute), CIBER Epidemiologica y Salud Pública (CIBERESP), Doctor Aiguader, 88, 08003 Barcelona, Spain8Institut Curie, Hôpital René Huguenin, 92210 Saint-Cloud, Paris9Institut Curie, Service d’Oncogénétique, 75005 Paris10Centre Léon Bérard, 69008 Lyon11Centre Paul Strauss, 67065 Strasbourg, France12Department of Genetic Medicine, St Mary’s Hospital, Manchester M13 9WL, UK13Oncogenetics Team, Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton, Surrey SM2 5PT, UK14Department of Clinical Genetics, East Anglian Regional Genetics Service, Addenbrookes Hospital, Cambridge CB2 0QQ15Department of Human Genetics, Radboud University Nijmegen Medical Centre, 6525 GA Nijmegen, Netherlands16Department of Clinical Genetics, Leiden University Medical Centre, 2333 ZA Leiden, Netherlands17Department of Medical Genetics, University Medical Centre Utrecht, 3584 CX Utrecht, Netherlands18Department of Clinical Genetics and Human Genetics, VU University Medical Centre, Amsterdam19Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah 84132, USACorrespondence to: F E van Leeuwen f.v.leeuwen{at}nki.nlAccepted 10 August 2012AbstractObjective 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.IntroductionExposure to ionising radiation is an established risk factor for breast cancer in the general population, with exposures in childhood and adolescence conferring a greater risk than exposure in adulthood.1 As BRCA1 and BRCA2 are involved in the repair of DNA double strand breaks,2 3 4 5 6 which can be caused by ionising radiation, it has been hypothesised that carriers of BRCA1/2 mutations might have increased radiosensitivity. Results of the few studies7 8 9 10 conducted so far on diagnostic radiation and risk of breast cancer among carriers have been inconsistent. Explanations for this inconsistency include differences in age at exposure and study limitations such as the investigation of a single type of diagnostic procedure (such as only chest radiography7 8 or only mammography9 10), a retrospective design with potential recall and/or survival bias,7 8 9 10 or sometimes relatively small numbers.8 9 In some countries the screening protocol for BRCA1/2 mutation carriers now recommends the avoidance of mammographic screening before age 30 and advises the use of non-ionising radiation imaging techniques (such as magnetic resonance imaging (MRI)) as the main tool for surveillance at young ages.We report on the BRCA1/2 mutation carrier study arm of the GENE-RAD-RISK project, a large European cohort study designed to examine whether variations in specific DNA repair genes increase the risk of breast cancer associated with radiation. Although the present study has a retrospective design, the association between diagnostic radiation and breast cancer risk in BRCA1/2 mutation carriers is unlikely to be investigated prospectively in the near future. This is because incident case numbers are not expected to increase rapidly because of the increasing uptake of prophylactic surgery among unaffected BRCA1/2 mutation carriers and the relatively short follow-up since DNA testing for BRCA mutations became available (1995), together with the fact that many newly identified carriers were tested because they (already) had breast cancer.MethodsStudy populationThe present study included 1993 women who were tested in a clinical setting (that is, at a clinical genetic centre), identified as carrying a pathogenic BRCA1 or BRCA2 mutation, and aged 18 or older. Women were recruited into the GENE-RAD-RISK cohort study in 2006-09 and were participants in three large ongoing national cohort studies of carriers in France (GENEPSO; n=716 (36%)), the UK (EMBRACE11; n=688 (35%)), and the Netherlands (HEBON12; n=589 (30%)).Each participant completed a standardised questionnaire (response rate 78%; see supplementary table A). Diagnoses of breast cancer were recorded through linkage with national registries or medical records.Exposure to diagnostic radiationParticipants reported their history of exposure to diagnostic radiation in a detailed questionnaire containing indication based questions on lifetime exposure to fluoroscopy, conventional radiography of the chest/shoulders, mammography, computed tomography of the chest/shoulders, and other diagnostic procedures that use ionising radiation (such as bone scans) involving the chest or shoulders. Each section of the questionnaire provided a detailed description of the procedure and its most common indications. For fluoroscopy, radiography, and mammography, we asked about ever/never exposure, age at first exposure, number of exposures before age 20, and at ages 20-29 and 30-39, and age at last exposure. For each of the other exposure types, participants reported the indication, age at exposure, and number of exposures.We estimated the cumulative breast dose as an approximation of breast dose in units of Gy. Nominal estimates of breast dose for fluoroscopy, radiography, mammography, and computed tomography were derived from a literature review of published studies and institutional reports assessing radiation dose delivered to the breast from radiological examinations and expert judgment by ITC, AK, FvL, and AP (table 1?). When possible, we restricted the selected studies and reports to European studies performed on large samples, representative of patients and radiology services. The cumulative breast dose estimate was the sum of the age and calendar specific number of self reported diagnostic procedures multiplied by nominal estimates of breast dose.View this table:View PopupView InlineTable 1 Estimated doses of radiation (in Gy) to breast of diagnostic radiographic procedures by time period Statistical analysisWe used a Cox proportional hazards model to calculate adjusted hazard ratios of breast cancer and 95% confidence intervals, with age (in years) as time scale and cumulative radiation exposure from diagnostic procedures as a time dependent variable lagged by five years to exclude procedures that could have been performed because of a diagnosis of breast cancer and exclusion of radiation dose that probably did not contribute to induction of breast cancer. All analyses were stratified for gene (BRCA1 and BRCA2), birth cohort (<1955, 1955-61, 1962-68, >1968), and country (UK, France, and the Netherlands), and clustered on family. Standard Cox regression leads to biased estimates of the hazard ratio because the women in this study were selected from high risk families qualifying for genetic testing. The disease status might therefore have increased the likelihood of ascertainment leading to an oversampling of affected women. To correct for this potential bias (testing bias), we used the weighted regression approach described by Antoniou et al.13 With this procedure, individuals are weighted according to certain sampling probabilities such that the observed weighted incidence rate agrees with the true incidence rate in a similar but unselected cohort. The value of the weight depends on the age interval in which the person’s follow-up ends—that is, weights were assigned for each mutation and age category based on incidence rates from a population based study.14 Case weights were consistently lower than 1, indicating that cases are oversampled in the study. By the weighted regression approach, hazard ratios are typically shifted away from the null value (=1) at the cost of some power (wider confidence intervals).We defined two types of analytical cohorts: the entire cohort and a subcohort. In the entire cohort analysis, follow-up started at birth and ended at the date of the first diagnosis of breast cancer (n=848), other cancers excluding basal cell carcinoma (n=96), date of bilateral prophylactic mastectomy (n=234), or completion of the questionnaire (n=815), whichever occurred first. There were 78?074 person years of observation. In all retrospective cohort studies that use questionnaire data, affected women who survived until questionnaire completion could fill out the questionnaire only because they have survived. If the exposure under investigation is associated with worse survival, cases without exposure would be more strongly represented, introducing bias to the null. Although little is known about the influence of exposure to ionising radiation, low or high dose, on overall survival and breast cancer specific survival in carriers, there are indications that breast cancer associated with radiation has a distinct, less favourable, gene expression profile.15 To correct for potential survival bias arising from the exclusion of exposed carriers who died from breast cancer long before questionnaire completion, we carried out our main analyses on relatively recent cases—that is, carriers who received diagnosis of a breast cancer or who were censored within the five years before completion of the questionnaire. Follow-up was counted only during this five year period and with a new set of period specific weights. This subcohort analysis contained a total of 1122 participants, 174 of whom had breast cancer. There were 4484 person years of observation. Although based on smaller numbers, we consider the results of the subcohort to be the most valid and have therefore presented these results in the main text. We have presented the results from the entire cohort in supplementary tables and briefly summarise them in the results section.As exposure to diagnostic radiation was reported in decades of age, we assumed that exposures were equally distributed across each decade, taking into account ages at first and last exposure. This resulted in the following categorisation for cumulative number of exposures: 1=0.5-1.4; 2=1.5-2.4; 3-4=2.5-4.4; >4=4.5 or more. The estimate of cumulative breast dose was categorised based on quarters of cumulative dose at age 40.We observed no violation of the proportional hazards assumption by any variable. Tests for trend of number of exposures were conducted by assigning to each individual the median of the number of exposures in each exposure category (rather than the individual’s reported number of exposures) and including this as a continuous variable in an unweighted procedure specific model. Missing values in ever/never exposure (<11%) and covariates (<1%) were coded as an additional category. Among carriers with any exposure to diagnostic radiation, missing values for age at first exposure (<15% for fluoroscopy and radiography and <10% for mammography) and last exposure (<5%) and number of exposures (<21% for fluoroscopy and radiography and <7% for mammography) were imputed by age period, with the mean age and number of exposures of women for whom complete data were available. Linear excess relative risks per Gy were estimated by unweighted conditional logistic regression with SAS code.16 We adjusted the risk estimates for the analyses of cumulative breast dose for parity and menopausal status. We adjusted analyses of radiography and mammography for age at menarche, parity, and menopausal status. Other potential confounding factors, including age at first full term pregnancy and breast feeding, did not change the log(hazard ratio) estimates by more than 10% and were omitted from final models. We examined effect modification by country, BRCA1 versus BRCA2, birth cohort, and attained age. Two sided P<0.05 was considered significant. Analyses were performed with Stata/SE 11.0 (StataCorp).ResultsIn the entire cohort, 43% (n=848) of carriers had received a diagnosis of breast cancer (table 2?; of these 89% (n=755) were confirmed by medical records or linkage with national registries. There was no difference between cases and unaffected carriers in age at diagnosis of breast cancer and age at censoring (mean 39.5 (SD 7.4) and 39.7 (SD 7.4) for cases and unaffected carriers respectively; P=0.601). Women with breast cancer, however, were older at questionnaire completion (49.7 (SD 8.6) v 42.1 (SD 10.5), P<0.001). In general, there were no differences in characteristics between the entire cohort and the subcohort, though the carriers in the subcohort were on average younger at questionnaire completion than those in the entire cohort (41.1 (SD 9.7) v 50.7 (SD 8.8), P<0.001).View this table:View PopupView InlineTable 2 Characteristics of entire cohort (n=1993) of BRCA1/2 mutation carriers and subcohort (n=1122) of relatively recent cases. Figures are numbers* (percentage) of participantsRadiography was the most common diagnostic procedure; 48% (n=919) of carriers reported ever having had a radiograph while 33% (n=649) had ever had a mammogram (table 3?). The median numbers of procedures before age 40 were 2.5 for radiography and 2.4 for mammography. The mean age at first mammogram was 29.5 (SD 5.8). Only a small proportion (<5%) of carriers were ever exposed occupationally, during pregnancy or during breast feeding, to computed tomography or other diagnostic radiation procedures (table 3). None of the carriers had received radiotherapy before the end of follow-up because cancers other than breast cancer were censored. The mean estimated cumulative breast dose from fluoroscopy, radiography, mammography, and computed tomography combined was 0.0140 Gy and ranged from 0.0005 to 0.6130 Gy (interquartile range 0.0020-0.0174 Gy).View this table:View PopupView InlineTable 3 Exposure to diagnostic radiation in entire cohort (n=1993) and subcohort (n=1122). Figures are numbers* (percentage) of participantsTable 4 shows the results of the analyses on cumulative breast dose and risk of breast cancer ?. When compared with no exposure, any exposure before age 30 was associated with an increased risk (hazard ratio 1.90, 95% confidence interval 1.20 to 3.00). We also observed a pattern of increasing risk with increasing dose; for a cumulative dose estimate of more than 0.0174 Gy we observed an almost fourfold increased risk of breast cancer (3.84, 1.67 to 8.79). A similar increased risk was observed for exposure before age 20 even after a lower dose of more than 0.0066 Gy (3.16, 1.19 to 8.39). There was no evidence of an increased risk of breast cancer associated with exposure at ages 30-39. The unweighted excess relative risks per Gy for exposures before ages 40 and 30 were 14.76 (P=0.138) and 29.81 (P=0.100).View this table:View PopupView InlineTable 4 Analyses of estimated cumulative breast dose of diagnostic radiation and risk of breast cancer for subcohort (n=1122) of BRCA1/2 mutation carriersIn the analysis of specific diagnostic procedures we observed a trend of increasing risk of breast cancer with increasing number of radiographs before age 20 (P=0.041 for trend) and a non-significantly increased risk of breast cancer after more than two fluoroscopies before age 20 (hazard ratio 2.01, 95% confidence interval 0.71 to 5.71, P=0.102 for trend) compared with no exposure (table 5 ?). Furthermore, there was a non-significantly increased risk of breast cancer after exposure to mammography before age 30 (1.43, 0.85 to 2.40, P=0.040 for trend). We observed an almost twofold risk increase for exposure to more than four radiographs before age 30 (1.83, 0.84 to 4.00, P=0.012 for trend) and for more than four radiographs at ages 30-39 (2.04, 0.85 to 4.90, P=0.101 for trend; data not shown), though this latter category included only six cases. We found no other associations between exposure at ages 30-39 and risk of breast cancer.View this table:View PopupView InlineTable 5 Analyses on different types of diagnostic procedures by age period and risk of breast cancer for subcohort of 1122 BRCA1/2 mutation carriersThe risk estimates presented in tables 4 and 5 were not materially affected by inclusion of the estimates for each age period (that is, <20, 20-29, and 30-39 years) in the same model or by adjustment for occupational exposure. The results of the procedure specific analyses did not change when we included different exposure types in one model. The results did not differ by country (data not shown). Use of a two or 10 year time lag did not materially affect the results (data not shown).A strong family history of breast cancer could be an indication for mammographic screening at a young age. We investigated this potential bias away from the null by a subgroup analysis of the cumulative breast dose in carriers who never had a mammogram before age 30 (table 6?). This resulted in a similar association compared with the complete model (table 4).View this table:View PopupView InlineTable 6 Analyses of estimated cumulative breast dose of diagnostic radiation before age 30 and risk of breast cancer for BRCA1/2 mutation carriers who had never undergone mammographyWe investigated whether there was a difference in the association between exposure to diagnostic radiation and risk of breast cancer for BRCA1 and BRCA2 carriers. Among BRCA1 carriers, any exposure before age 30 was associated with an increased risk (hazard ratio 2.83, 95% confidence interval 1.59 to 5.04) and the following pattern of dose-response emerged: risks for cumulative dose estimates of <0.0020 Gy, =0.0020-0.0065 Gy, =0.0066-0.0173 Gy, and =0.0174 Gy were 2.46 (1.27 to 4.77), 2.45 (1.02 to 5.90), 2.72 (0.99 to 7.44), and 5.00 (1.96 to 12.74), respectively. For BRCA2 carriers we did not observe an association in the subcohort, but this analysis was limited because of the small number of cases. The P value for interaction between gene and ever versus never exposure before age 30 was 0.631. We also evaluated risk associated with exposure before the age of 30 by attained age below and above the median of 40 to examine the effect of time since exposure. We observed a non-significant higher risk for the younger attained age group compared with the older age group (1.87 (1.13 to 3.10) v 1.64 (1.00 to 2.68), respectively). We observed no effect modification by birth cohort (P>0.05 for interaction; data not shown).In the entire cohort, a history of any exposure before age 30 was also associated with a significantly increased risk (hazard 1.39, 1.12 to 1.73) but no dose-response emerged (supplementary table B). The association with exposure before age 20 was similar (1.37, 1.11 to 1.68), with some indication of a dose-response. There was no evidence of an increased risk of breast cancer associated with exposure at ages 30-39. The unweighted excess relative risks per Gy for exposures before ages 40 and 30 were 3.90 (P=0.121) and 5.54 (P=0.107). In the analysis of specific diagnostic procedures we found no significant associations between specific procedures and risk of breast cancer (supplementary table C). Based on only a few cases, exposure to computed tomography before age 30 seemed to be associated with increased risk of breast cancer (2.36, 0.71 to 7.88).DiscussionPrincipal findingsIn this large European study, exposure to diagnostic radiation before age 30 was associated with an increased risk of breast cancer in BRCA1/2 mutations, at dose levels considerably lower than those at which increases have been found in other cohorts exposed to radiation. We estimated the cumulative breast dose from various exposures to diagnostic radiation and observed increases in risk for exposure before age 30, even for a relatively low dose category (that is, below 0.0066 Gy0. No association with risk of breast cancer was apparent for exposure at ages 30-39.Comparison with other studiesTwo previous studies among women with BRCA1/2 mutations who had undergone mammography observed no association with risk of breast cancer.9 10 This could be because of the relatively high age at first mammogram, which was on average 35, while in our study it was 29.5 (SD 5.8) years. We observed a 1.4-fold increased risk of breast cancer after mammography before age 30 with a (non-significant) pattern of dose-response (table 5). We were concerned that this latter association might be attributed to confounding by indication—that is, self selection for early mammography in carriers with a strong family history of breast cancer. This was not the case as the association between cumulative breast dose and risk of breast cancer remained after we excluded carriers who had had mammography (table 6). Confounding by indication on the other diagnostic procedures is highly unlikely.Two other studies have reported an association between self reported exposure to chest radiography and risk of breast cancer in BRCA carriers.7 8 Risks were particularly high among those exposed before age 20. Some of our participants (21%) were also included in one of these previous studies, the IBCCS.7 In their subcohort, the IBCCS reported a 1.8-fold increased risk while we observed a 1.4-fold non-significantly increased risk (hazard ratio 1.38, 95% confidence interval 0.87 to 2.20; data not shown) for exposure to radiography. This difference could be explained by the fact that we excluded radiographs received after age 40 and less than five years before diagnosis while the IBCCS had included all lifetime radiographs, including those after diagnosis of breast cancer. Exclusion of the overlapping group did not materially affect our results.We hypothesised that BRCA carriers could have increased radiosensitivity because of impaired DNA repair mechanisms. We observed increased risks of breast cancer among BRCA1/2 mutation carriers at dose levels considerably lower than those at which increases have been found in other cohorts exposed to radiation. A pooled analysis of eight cohorts exposed to radiation estimated a relative risk of about 2.0 at a dose of 1 Gy, assuming an age at exposure of 25 years.17 Nowadays, the dose estimate to the breast from a two view mammogram is in the order of 4 mGy. Even in women who reported undergoing a large number of mammograms, the total radiation dose to the breast is unlikely to exceed 20 mGy. This corresponds to a predicted relative risk of less than 1.02 based on the Preston model, which is substantially less than the risk estimates we observed.In the general population, a minimal induction time for breast cancer of 10 to 15 years after exposure to radiation is generally accepted, with relative risks decreasing as a function of attained age after reaching a peak, usually between the age of 30 and 40.17 18 As we hypothesised that BRCA carriers could have increased radiosensitivity because of impaired DNA repair mechanisms, we used a five year time lag in our analyses. Analyses with a two or 10 year time lag showed similar results (data not shown). Analyses stratified by attained age (=40 v >40) showed no significant effect modification. In line with published literature19 we observed a slightly stronger risk for the younger attained age group. It is possible that we did not see a strong effect of attained age because of limited variation in attained age in our study population. Alternatively, it could be that the attained age/time since exposure effect in BRCA1/2 carriers differs from that in the general population.Strengths and limitationsSeveral strengths and weaknesses of our study should be considered in the interpretation of these results. The strengths of our study include the sample size and the detailed information on all diagnostic procedures that used ionising radiation in different age periods. While previous studies7 8 9 10 were based only on mammography or radiography, we also investigated types of diagnostic exposures other than mammography and radiography in carriers and calculated one estimate of total radiation dose. The weighted cohort approach was used to overcome testing bias. The changes of the hazard ratios from the weighting (see supplementary tables C and D) were relatively small and in the expected direction, so the weights seem to meet their purpose of taking away some testing bias. The weighting procedure does not have any impact on the interpretation of the results. The retrospective nature of our study, however, might have caused recall bias. We relied on self reports rather than review of medical records because of the difficulties in accessing medical records with regard to the various diagnostic procedures. These took place for many different indications and many occurred in the distant past. Two methodological studies in the Dutch cohort (test-retest reliability20 and validity21 of self reported diagnostic radiation) showed that the extent of the observed misclassification was small and mainly non-differential by disease status, consistent with other studies.22 23 24 25 In the validation study, for example, the proportion agreement and ? for ever/never having had a mammogram before age 30 was >90% and >0.80, respectively, and this was not different between cases and unaffected carriers (P=0.237).21 Therefore, recall bias seems unlikely in our study and the observed non-differential misclassification might have biased our results towards unity. Non-differential misclassification could also have occurred because exposure before age 10 is unlikely to have been recalled by women. Also, exposure before age 20 is more difficult to recall than exposure at higher and thus more recent ages. Therefore, in our study, exposure before age 20 could have been prone to more non-differential misclassification than exposure at ages 20-29. This might explain the similar relative risks observed for both age groups, in contrast with what was observed in radiation exposed cohorts that did not rely on self reports.1 17 Furthermore, our follow-up might not have been long enough to detect an association between radiation exposure at ages 30-40 and risk of breast cancer.The calculation of the cumulative dose estimate was based on several assumptions. Firstly, we did not use indication specific dose estimates for fluoroscopy and radiography. Most (>95%) fluoroscopies before age 20, however, were chest fluoroscopies for tuberculosis screening and originated from the Dutch cohort (where mass population screening for tuberculosis in young people was performed 1940-6026). For radiography before age 20, most (>90%) were chest radiographs for which the dose (0.0005 Gy) differed from the dose of shoulder radiography for exposures before 1974 only (0.0010 Gy).27 Secondly, we dealt with missing values by single stratified mean imputation or by including a separate category. We think that this did not influence our results because the proportion of missing values was not different for cases and unaffected carriers. Moreover, missing values were imputed only if the exposure was known to have occurred in the relevant age period. Thirdly, we assumed that differences in dose estimates between the three European countries would be small as the recent country specific dose estimates for mammography for the UK and the Netherlands were similar. Nevertheless, for all types of diagnostic procedures, large differences might exist between machines and hospitals. Fourthly, the dose estimates for mammography were based on a two view mammogram. The doses used are typical doses for an average woman, but there are large variations depending on several characteristics of patients (such as breast size) and parameters of the equipment. Finally, we assumed the breast dose estimate reflected breast dose, assuming that the estimates reflect absorbed dose to fibroglandular tissue. This might apply only to mammography because those estimates were derived from entrance surface dose to dose to fibroglandular tissue. But we doubt that this is the case for the other diagnostic procedures.The assumptions regarding cumulative dose estimate and the previously discussed non-differential misclassification, together with the small number of cases in some analyses, could have contributed to a lack of consistent dose-response trends. We consider that it is unlikely that there is no true effect because the overall pattern indicates increased risks; hazard ratios are already increased, albeit non-significantly for the lowest dose category, and remain increased for all categories of higher dose.The stronger associations observed in the subcohort compared with the entire cohort are intriguing and suggest survival bias in the entire cohort. Although little is known about the influence of exposure to ionising radiation at low or high doses on overall survival and breast cancer specific survival in carriers, one study showed that radiation associated breast cancer had a distinct, less favourable, gene expression profile.15 Another explanation for the differences between the two analytical cohorts could be more non-differential misclassification in the entire cohort, in which the mean age at questionnaire completion was higher than in the subcohort (50.7 (SD 8.8) and 41.1 (9.7) years, respectively, P<0.001). Older age at questionnaire completion was a significant predictor of the proportion of disagreement in the test-retest reliability study.20 Although based on a smaller number, we consider the results from the subcohort to be the most valid because they are unlikely to be affected by survival bias. A prospective analysis was not possible because the number of incident cases was too small (n=11). Incident case numbers in our study and others studies are not expected to increase rapidly because of the increasing uptake of prophylactic surgery in unaffected carriers and the relatively short follow-up since DNA testing became available (1995), together with the fact that many newly identified carriers were tested because they (already) had breast cancer.Unanswered questions and future researchThe linear non-threshold model is widely accepted to also apply to estimation of risk after low doses and is used in radiation protection.28 29 Linear non-threshold extrapolation, however, might not apply to groups with a genetic susceptibility for increased radiosensitivity. Also, a few studies seem to show some differences in the biological responses to high and low dose radiation.30 Our data are inconsistent with a threshold. The category specific hazard ratios (1.00 (reference), 1.6, 1.8, 1.8, and 3.8 for dose categories <0.002, 0.002-0.0065, 0.0066-0.0173, and =0.0174 Gy, see table 4, exposure before age 30) are already increased, albeit non-significantly, for the lowest dose category and remain increased for all categories of higher dose. When we evaluated curvature by adding quadratic dose to a model with continuous dose, there was some evidence for concavity—that is, downward curvature (P=0.009 for quadratic term). Because there are relatively few cases in the high dose range, this result must be interpreted with caution. The possibility of a dose-response relation other than linear warrants further investigation.To indicate the clinical relevance of our results we calculated the absolute risk of breast cancer for exposure before age 30. Nowadays, the glandular dose of a single two view mammogram is around 4 mGy. This falls into the second dose category (0.0020-0.0065). According to our study results, the hazard of breast cancer associated with a mammogram taken between age 20 and 29 was 1.55 (95% confidence interval 0.76 to 3.17; see table 4). For a 30 year old carrier, the risk of developing breast cancer at age 40 (mean age at diagnosis in our study) is about 9% (assuming a 2:1 ratio of BRCA1 and BRCA2).31 This means that among 100 carriers aged 30, nine will have developed breast cancer by age 40. The absolute number of cases would increase by five ((1.55×9)-9) if all had had one mammogram before age 30. Because of the previously described study limitations and because currently there are no definitive international baseline mutation specific estimates of penetrance for risk of breast cancer among BRCA1/2 mutation carriers, however, this estimate should be interpreted with caution.An interesting finding is the difference we observed in the association between exposure to diagnostic radiation and risk of breast cancer for BRCA1 and BRCA2 carriers. For age specific exposure effects, however, the power in the BRCA2 group was rather low. Future studies should focus on prospective follow-up and examine modifying effects by genotype in larger populations, for exposure to both low and high dose ionising radiation.Conclusions and policy implicationsIn conclusion, in this large European study among BRCA1/2 mutation carriers, 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 recommendation to use non-ionising radiation imaging techniques (such as MRI) as the main tool for surveillance in young BRCA1/2 mutation carriers.What is already known on this topicEpidemiological studies on the association between diagnostic radiation and risk of breast cancer in BRCA1/2 mutation carriers have inconclusive results, possibly because of limitations such as the investigation of a single type of diagnostic procedure, relatively small numbers and lack of dose estimates, and a retrospective design with potential recall and survival biasWhat this study addsIn BRCA1/2 mutation carriers, exposure to diagnostic radiation before the age of 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 radiationWhile previous studies were based only on mammography or radiography, this large cohort study used estimates of an individual age specific cumulative breast dose from various diagnostic radiation procedures as a measure of total diagnostic radiation exposure The results support the use of non-ionising radiation imaging techniques (such as MRI) for surveillance in young with BRCA1/2 mutationsNotesCite this as: BMJ 2012;345:e5660FootnotesWe thank Vanessa Tenet, Claude Picard, Irwin Piot, Esther Janssen, Monica Legdeur, Josette van As, and Renée Mulder for their help in data collection, entry, and cleaning; D Richardson and M Schaapveld for their help with the analysis of excess relative risks; M Bleiker and S Muller for their advice on dosimetry issues; Lesley Richardon for assistance in the design and conduct of the Gene-Rad-Risk study; and Dillwyn Williams for his support and advice on the EMBRACE radiation history study.Centres and individuals of the three nationwide studiesGENEPSO (Gene Etude Prospective Sein Ovaire, France)Coordinating Centre, Centre René Hugenin, Saint Cloud: Catherine Noguès, Emmanuelle Fourme, Rosette Lidereau, Denise Stevens; Institut Curie, Paris: Dominique Stoppa-Lyonnet, Marion Gauthier-Villars; Institut Gustave Roussy, Villejuif: Agnès Chompret; Centre René Huguenin, Saint Cloud: Catherine Noguès; Centre Paul Strauss, Strasbourg: Jean-Pierre Fricker; Centre François Baclesse, Caen: Pascaline Berthet; Centre Alexis Vautrin, Vandoeuvre-les-Nancy: Elisabeth Luporsi; Centre Léon Bérard, Lyon: Christine Lasset, Valérie Bonadona; Centres Paul Papin, René Gauducheau, and Catherine de Sienne, Angers, Nantes: Alain Lortholary; Centre Antoine Lacassagne, Nice: Marc Frénay; Hôpital D’Enfants Centre Hospitalier Universitaire, Dijon: Laurence Faivre; Institut Paoli-Calmettes, Marseille: Hagay Sobol, François Eisinger, Laetitia Huiart; Institut Bergonié, Bordeaux: Michel Longy; Institut Jean Godinot, Reims: Tan Dat Nguyen; Institut Claudius Regaud, Toulouse: Laurence Gladieff, Rosine Guimbaud; Centre Hospitalier Georges Renon, Niort: Paul Gesta; Centre Oscar Lambret, Lille: Philippe Vennin, Claude Adenis; Hôpital Charles Nicolle, Centre Henri Becquerel, Rouen: Annie Chevrier, Annick Rossi; Centre Jean Perrin, Clermont-Ferrand: Yves-Jean Bignon; Hôpital Civil, Strasbourg: Jean-Marc Limacher; Centre Eugène Marquis, Rennes: Catherine Dugast; Polyclinique Courlancy, Reims: Liliane Demange; Hôpital de la Timone, Marseille: Hélène Zattara-Cannoni; Clinique Sainte Catherine, Avignon: Hélène Dreyfus; Centre Hospitalier Universitaire Arnaud Villeneuve, Montpellier: Mehrdad Noruzinia; and Centre Hospitalier Régional et Universitaire Dupuytren, Limoges: Laurence Venat-Bouvet.EMBRACE (Epidemiological Study of BRCA1 and BRCA2 mutation carriers, UK)Coordinating Centre, Cambridge: Susan Peock, Margaret Cook, Debra Frost, Clare Oliver; North of Scotland Regional Genetics Service, Aberdeen: Helen Gregory; West Midlands Regional Clinical Genetics Service, Birmingham: Trevor Cole, Lucy Burgess; East Anglian Regional Genetics Service, Cambridge: Joan Paterson; Medical Genetics Services for Wales, Cardiff: Mark Rogers, Lisa Hughes; Peninsula Clinical Genetics Service, Exeter: Carole Brewer; West of Scotland Regional Genetics Service, Glasgow: Rosemarie Davidson, Nicola Bradshaw; South East Thames Regional Genetics Service, London: Louise Izatt, Gabriella Pichert, Caroline Langman; Yorkshire Regional Genetics Service, Leeds: Carol Chu, Julie Miller; Manchester Regional Genetics Service, Manchester: Gareth Evans, Fiona Lalloo, Andrew Shenton; Oxford Regional Genetics Service, Oxford: Lucy Side; Department of Cancer Genetics, Royal Marsden NHS Foundation Trust: Ros Eeles, Elizabeth Bancroft, Elizabeth Page, Elena Castro, Audray Ardern-Jones, Richard Houlston, Nazneen Rahman, Susan Shanley; North Trent Clinical Genetics Service, Sheffield: Jackie Cook, Lauren Baxter; South West Thames Regional Genetics Service, London: Shirley Hodgson, Sheila Goff; and Wessex Clinical Genetics Service, Southampton: Diana Eccles. Gareth Evans and Fiona Lalloo are supported by an NIHR grant to the Biomedical Research Centre, Manchester. The investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles and Elizabeth Bancroft are also supported by Cancer Research UK Grant C5047/A8385.HEBON (Netherlands Collaborative Group on Hereditary Breast Cancer, Netherlands)Coordinating center: Netherlands Cancer Institute, Amsterdam: Senno Verhoef, Anouk Pijpe, Richard Brohet, Frans Hogervorst, Laura van ‘t Veer, Flora van Leeuwen, Matti Rookus; Erasmus Medical Center, Rotterdam: Margriet Collée, Ans van den Ouweland, Mieke Kriege, Mieke Schutte, Maartje Hooning, Caroline Seynaeve; Leiden University Medical Center, Leiden: Rob Tollenaar, Christi van Asperen, Juul Wijnen, Peter Devilee; Radboud University Nijmegen Medical Centre, Nijmegen: Nicoline Hoogerbrugge, Marjolijn Ligtenberg; University Medical Center Utrecht, Utrecht: Margreet Ausems, Rob van der Luijt; Amsterdam Medical Center: Cora Aalfs, Theo van Os; VU University Medical Center, Amsterdam: Hanne Meijers-Heijboer, Hans Gille; University Hospital Maastricht, Maastricht: Encarna Gomez-Garcia, Rien Blok; University Medical Center Groningen, Groningen: Jan Oosterwijk, Annemiek van der Hout; Netherlands Foundation for Detection of Hereditary Tumours, Leiden: Hans Vasen, Inge van Leeuwen.Contributors: AP, NA, DFE, AK, EC, DG, FEvL, and MAR were responsible for study concept and design. AP, DFE, CN, MG-V, CL, J-PF, SP, DF, DGE, RAE, JP, PM, CJvA, MGEMA, HM-H, IT-C, and MAR acquired the data. AP, NA, DFE, AK, MH, FEvL, and MAR analysed and interpreted the data. AP, NA, DFE, AK, FEvL, and MR drafted the manuscript, which was critically revised for important intellectual content by all authors. AP, NA, DFE, AK, MH, FEvL, and MR carried out the statistical analyses. NA, DFE, EC, CN, MAR, and FEvL obtained funding. AP, NA, DFE, AK, EC, CN, SP, PM, MAR, and FEvL supervised the study. All authors commented on and approved the final draft. FEvL is guarantor.Funding: The GENE-RAD-RISK study was supported by grant No 012926 (FI6R) under Euratom Programme; GENEPSO: Fondation de France and Ligue National Contre le Cancer; EMBRACE: Cancer Research UK (grant C1287/A10118 and C1287/A8874); HEBON: Dutch Cancer Society (grants NKI1998-1854, NKI2004-3088, NKI 2007-3756). DFE is a principal research fellow of Cancer Research UK. The sponsors had no role in the design of the study; in the collection, analysis, and interpretation of the data; in the writing of the report; and in the decision to submit the paper for publication.Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: DFE is board member of Genome Canada. RAE receives royalties for the book Genetic Predisposition to Cancer, has received educational grants from Tepnel, Illumina, and Vista Diagnostics and has received honoraria for BRCA-related lectures from MD Anderson and University of Southampton. DG receives royalties from BRCA1 testing.Ethical approval: The study was approved by the medical ethics committees of all participating centres (Commission nationale de l’informatique et des libertés, France; Cambridgeshire 4 Research Ethics Committee; Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam), and all participants provided written informed consent.Data sharing: No additional data available.This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.References?Ronckers CM, Erdmann CA, Land CE. Radiation and breast cancer: a review of current evidence. 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View larger version:In a new windowDownload as PowerPoint SlideFig 1 Inclusion of patients in studyAmong the 55?297 women who had primary breast conserving surgery, 45?793 (82.8%) had isolated invasive disease, 6622 (12.0%) had isolated in situ disease, and 2882 (5.2%) had both invasive and in situ disease coded in their primary breast conserving surgery record. Thus, a total of 9504 (17.2%) women had a carcinoma in situ component recorded at the time of the primary breast conserving surgery.Reoperation rates after primary breast conserving surgeryIn the three months after primary breast conserving surgery, 11?032 (20.0%, 95% confidence interval 29.6% to 20.3%) of the 55?297 women had at least one breast reoperation. Of these, 10?212 women had one reoperation—5943 had further breast conserving surgery, and 4269 had a mastectomy, corresponding to rates of 10.7% (10.5% to 11.0%) and 7.7% (7.5% to 7.9%). The remaining 820 (1.5%, 1.4% to 1.6%) women had two or more reoperations. This means that, of the 5943 women who had a second breast conserving procedure, 13.8% (12.9% to 14.7%) were again found to have inadequate margins and needed at least one more reoperation.Reoperation rates differed between women with and without carcinoma in situ coded (table 1?). Women with a carcinoma in situ component coded were more likely to have at least one reoperation (29.5% v 18.0%, P<0.001). Among women who had just one reoperation, the proportion that had mastectomy rather than a second breast conserving procedure was not associated with whether or not their tumours had a carcinoma in situ component coded (41.6% v 41.9%, P=0.77).View this table:View PopupView InlineTable 1 Patterns of breast reoperation within three months of primary breast conserving surgery, categorised by type of tumourReoperation was less likely in older women and in those with more comorbid conditions (table 2?). Reoperation rates were marginally lower among women from more deprived areas. The increased risk of reoperation among women with a carcinoma in situ component coded persisted after adjustment for these factors (adjusted odds ratio 1.9, 95% confidence interval 1.8 to 2.0).View this table:View PopupView InlineTable 2 Proportions of women having breast reoperation after primary breast conserving surgery in English NHS hospital organisations between 2005 and 2008Reoperation rates at individual NHS trustsOne hundred and forty-eight English NHS trusts did more than 30 primary breast conserving surgery procedures over the three year period (the “minimum volume” criterion excluded 58 women). We excluded a further 306 women for whom information about their age and deprivation category was missing (table 2?).The reoperation rate among women who had breast conserving surgery varied significantly across the 148 trusts (fig 2?); the 10th and 90th centiles of the rates were 12.4% and 29.5%. The effect of adjusting the reoperation rates for patients’ characteristics (age at admission, tumour group, comorbidity, and socioeconomic deprivation) differed across the trusts; 11 values changed by an absolute value of at least 2%. However, this did not reduce the between trust variation overall (fig 3?). The 10th and 90th centiles of the adjusted reoperation rates were 12.2% and 30.2%. We found no evidence that reoperation rates were related to the level of activity at an NHS trust.
View larger version:In a new windowDownload as PowerPoint SlideFig 2 Unadjusted breast reoperation rates in English NHS acute hospital organisations for women who had breast conserving surgery for breast cancer between 2005 and 2008. BCS=breast conserving surgery
View larger version:In a new windowDownload as PowerPoint SlideFig 3 Risk adjusted breast reoperation rates in English NHS acute hospital organisations for women who had breast conserving surgery for breast cancer between 2005 and 2008. BCS=breast conserving surgeryDiscussionReoperation after breast conserving surgery for breast cancer can result in a poorer cosmetic outcome compared with mastectomy, and evidence shows that reoperation is associated with increased rates of local and distant recurrence.7 27 28. One in five women who had primary breast conserving surgery in the English NHS between April 2005 and March 2008 needed a breast reoperation within three months. Moreover, among women who had breast conserving surgery as a reoperation, one in seven needed further surgery. Reoperation was more common among women with a carcinoma in situ component recorded at the time of the primary breast conserving surgery than in those without (29.5% v 18.0%). It was also more common among younger women.A fourfold variation existed in the reoperation rate between the English NHS trusts. This raises questions about the uniformity of the selection criteria for both primary breast conserving surgery and reoperation, and it highlights the need for cancer networks and professional organisations to develop initiatives aimed at reducing the risk of reoperation. The current situation is unsatisfactory as it results in women having experiences of care that depend on where they are treated. This is of concern because around 40% of women who had a reoperation after breast conserving surgery ended up having a mastectomy. The reasons for the lower rates of reoperation at particular NHS trusts should be explored so that lessons can be learnt and disseminated.Strengths and limitations of studyOur study has several strengths. It used a comprehensive national database, which reduces the risk of selection bias. We focused on breast reoperation rates and did not include subsequent operations to the axilla, and we required primary and subsequent procedures to have the same laterality to avoid including contralateral procedures as reoperations. We chose to estimate reoperation rates by provider and not by surgical team, because NHS trust is reliably coded in hospital episode statistics, whereas the coding of surgical team has not been validated, and because the volume of activity at the level of the surgeon would give limited statistical precision. Finally, the timeframe for classifying subsequent procedures as reoperation avoided inclusion of operations for complications or for early local recurrence. As a sensitivity analysis, follow-up was extended to six months (used by some studies), and we found that this had little effect: the overall reoperation rate increased from 20.0% to 20.6%.The hospital episode statistics database does not include records of treatment in private hospitals, and a small number of women who have their primary breast conserving surgery in an NHS hospital would have had a therapeutic reoperation in a private hospital. This migration will have lowered our estimates of overall reoperation rates, although the degree of underestimation is likely to be minimal. The effect on the rates of NHS trusts is also likely to be small compared with the variation observed.Another limitation is the potential for inaccuracies in the coding of diagnoses and procedures within hospital episode statistics.29 Reoperation rates would be affected by the omission or miscoding of the procedure and laterality of the operation. However, validation work done for breast cancer surgery suggests that procedure codes in hospital episode statistics are accurate, with 90-93% agreement with data provided by surgeons across English regions.30 We used a wide range of codes to identify reoperations to minimise the effect of coding errors on the observed reoperation rate. As a result, we expect the overall effect of coding errors to be small.Our results would be influenced by the accuracy of the coding of a carcinoma in situ component. Clinical coding teams record information on diagnosis (C50, D05, or both) based on preoperative biopsy findings initially and then amend these diagnoses, if necessary, after receipt of the definitive postoperative histology results. In other words, we categorised women on the basis of their postoperative diagnosis, whereas decisions about whether to do breast conserving surgery were based on the histological diagnosis available before surgery. Overall, 17% of women in the hospital episode statistics were coded as having carcinoma in situ. This is similar to another large retrospective study,31 although other studies have reported higher prevalence rates.32 Such misclassification would result in an overestimate of the reoperation rate among women with only invasive disease, and the relative risk between the risk of reoperation and the presence of carcinoma in situ would be underestimated owing to “regression dilution.”33Finally, the hospital episode statistics database does not contain information on some potential confounders such as lobular histology, location and size of tumour, mammographic density, and lymphovascular invasion.7 27 34 Omission of these factors from the risk adjustment model could reduce its discriminatory performance. However, differences in the prevalence of these characteristics among NHS trusts are unlikely to account for the large variation observed between organisations.Comparison with other studiesReported reoperation rates after primary breast conserving surgery vary considerably. Some single centre series found rates varying from 17% to 68%.15 16 17 18 31 34 The UK NHS Breast Screening Programme reported a 22% therapeutic reoperation rate for invasive disease and a 26% rate for isolated non-invasive disease among a sample of UK surgeons in 2007-08.10 The UK All Breast Cancer report reported that 20% of patients with invasive disease and 29% of women with non-invasive disease had repeat operations.28 Overseas, a study from the Netherlands which combined data from 16 hospitals on 961 patients reported a reoperation rate of 28.9%; around 50% of these reoperations were mastectomies.18 Using data on 2206 women who had invasive disease from four specialist centres in the United States, another study reported that 23% of women had one reoperation, 9% had two reoperations, and 1% had three reoperations.31 A study from Germany of 565 women reported an overall reoperation rate of 21.4% and rates of 10% and 29% for women with and without an in situ component.34Comparing the results of studies on reoperation rates after breast conserving surgery is hampered by differences in the enrolled populations and variable definitions, particularly across studies from different countries.18 Our results are broadly similar to those of other UK and international studies, but caution is needed owing to methodological differences. The NHS Breast Screening Programme was based on women with cancers detected by screening, who are likely to have relatively small tumours with a lower grade and stage. The All Breast Cancer report (which combined cancer registry and hospital episode statistics data) included all primary operations (breast conserving surgery and mastectomy) for men and women diagnosed as having breast cancer, and the derivation of repeat operation included axillary surgery as well as re-excision of breast tissue.Implications of our findings for clinical practiceBreast conserving surgery followed by radiotherapy has been shown to give the same survival benefit as mastectomy for women with localised tumours.6 The choice between breast conserving surgery and mastectomy therefore depends on balancing the need to achieve complete excision of the tumour with patients’ preferences about cosmetic appearance. Clinical factors that influence this choice include the type, location, and spread of the tumour, multifocal disease, the ratio of tumour size to breast size, and the use of neoadjuvant systemic treatment.18 Our results highlight the importance of women also being made aware of the local rates of reoperation after primary breast conserving surgery when choosing their primary treatment, along with the likelihood of proceeding to mastectomy. In addition, our results emphasise the importance of offering mastectomy with immediate breast reconstruction as an alternative primary treatment option to women unless significant comorbidity or planned adjuvant treatment precludes this option.6 This option preserves the breast mound while making further therapeutic reoperation extremely unlikely.An important finding of our study is that reoperation rates after breast conserving surgery were higher in women with a carcinoma in situ component recorded at the time of their primary surgery. Although postoperatively identified carcinoma in situ at the invasive tumour margin is generally accepted to be a cause of inadequate surgical margins,6 women in this study without an invasive component must have had their in situ disease identified preoperatively. This suggests that the problem partly relates to difficulties in identifying the extent rather than just the presence of carcinoma in situ, because many such tumours are multifocal.7 35 Greater use of imaging techniques, such as whole breast ultrasonography,9 may help to reduce this problem.Interpreting variation in reoperation rates between English NHS trustsOur study showed that some English NHS trusts had adjusted reoperation rates below 10%, whereas for others it was above 30%. The variation was evident across NHS trusts that had low, medium, and high levels of activity, and we found no evidence of a volume-outcome relation. Surgery for early breast cancer is regarded as “preference sensitive” care, in which between provider variation may be legitimate because it reflects patients’ preferences for alternative treatment options.36 For this reason, expecting all NHS trusts to have the same underlying reoperation rate would be unreasonable. However, the variation is sufficiently large to suggest that it reflects differences in clinical practice at various points during the therapeutic pathway, as well as patients’ preferences. Practice related causes of variation could include differences in selection protocols for breast conserving surgery, poor surgical technique, and differences in how resection margins are assessed (although the effect of this last could be small given the national pathology reporting guidelines6). Nonetheless, the worse outcomes associated with reoperation mean that efforts are needed to reduce the risk of it occurring. As discussed above, this may come from improved imaging. The systematic practice of cavity margin resection has also been advocated as a means to reduce the likelihood of surgical re-excision.37An important cause of variation among these clinical factors is probably the lack of consensus on what constitutes an adequate excision margin, particularly when adjuvant radiotherapy is planned. The US National Cancer Institute has questioned the need for completely clear microscopic margins in breast conserving surgery,38 whereas the National Institute for Health and Clinical Excellence in England has recommended a minimum 2 mm radial excision margin for ductal carcinoma in situ but has not recommended margins for invasive disease.6 In Canada, national guidelines apply only to invasive disease and recommend that margins are microscopically clear and that any involved margins should be re-excised.39 This lack of consensus also affects research in this area, as studies adopt varying definitions of positive margin status.40 The uncertainty about adequate excision margins has led the Association of Breast Surgery to recommend that UK hospitals should develop their own local protocols for reoperation.41 Research is urgently needed on how different approaches of dealing with incomplete margins influence the likelihood of local recurrence.For these reasons, interpreting these reoperation rates derived from hospital episode statistics as indicators of the quality of care at individual trusts cannot be justified. Information on local protocols is lacking, and data on potential confounders is too limited in hospital episode statistics.26 In addition, data on rates of local recurrence are unavailable, and NHS trusts with low reoperation rates as well as those with high rates could have higher rates of recurrence. We suggest that the rate of reoperation would be a reliable measure of hospital performance only if it is derived in the context of a national clinical audit that has the requisite data items.ConclusionJust over half of women diagnosed as having breast cancer in England now select breast conserving surgery as their primary treatment. Cosmetic outcomes after surgery for breast cancer are an important consideration, and women should be made aware of the local rates of reoperation after primary breast conserving surgery, along with the likelihood of proceeding to mastectomy. In addition, breast cancer teams should do a local review of surgical technique, the definition of an adequate excision margin, imaging methods, and criteria for selecting patients. This may lead to an overall reduction in the reoperation rate after breast conserving surgery.What is already known on this topicMore than half of the 45?000 women diagnosed as having breast cancer in England have breast conserving surgery (BCS)BCS may result in incomplete excision of the tumour, which typically requires women to have either another breast conserving procedure or a mastectomyStudies on the rate of reoperation after BCS have been uncommon, and estimated rates vary from 17% to 68%What this study addsOne in five women who had primary BCS in the English NHS between April 2005 and March 2008 needed at least one breast reoperation within three months; about 40% of these had a mastectomyReoperation was more common among women with a carcinoma in situ component recorded at the time of the primary BCS than in those with isolated invasive carcinoma (29.5% v 18.0%)Reoperation rates varied substantially between NHS trusts, raising questions about the uniformity of the selection criteria for both primary BCS and reoperationNotesCite this as: BMJ 2012;345:e4505FootnotesWe thank the Department of Health for providing the hospital episode statistics data used in this study.Contributors: RJ, DAC, GL, and OK conceived the study. RJ, DAC, GL, OK, JHPvdM, JP, CS, and CMC designed the study. MT and DAC did the statistical analyses. RJ, DAC, and JHPvdM wrote the manuscript. MT, GL, OK, JP, CS, and CMC commented on and revised drafts. DAC is the guarantor.Funding: This study was not commissioned. JHPvdM received a national public health career scientist award from the Department of Health and NHS research and development programme.Competing interests: All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.Ethical approval: The study is exempt from UK National Research Ethics Committee approval as it involved analysis of an existing dataset of anonymised data for service evaluation. Approvals for the use of hospital episode statistics data were obtained as part of the standard hospitals episode statistics approval process.Data sharing: No additional data available.This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.References?Ferlay J, Autier P, Boniol M, Heanue M, Colombet M, Boyle P. Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol2007;18:581-92.OpenUrlFREE Full Text?American Cancer Society. Breast cancer facts and figures 2009-2010. American Cancer Society, 2009.?Office for National Statistics. 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