Diagnostic chest x-rays and breast cancer risk before age 50 years for BRCA1 and BRCA2 mutation carriers

Abstract

Background

The effects of low-dose medical radiation on breast cancer risk are uncertain, and few studies have included genetically susceptible women, such as those who carry germline BRCA1 and BRCA2 mutations.

Methods

We studied 454 BRCA1 and 273 BRCA2 mutation carriers aged <50 years from three breast cancer family registries in the USA, Canada, and Australia/New Zealand. We estimated breast cancer risk associated with diagnostic chest x-rays by comparing mutation carriers with breast cancer (cases) with those without breast cancer (controls). Exposure to chest x-rays was self-reported. Mammograms were not considered in the analysis.

Results

After adjusting for known risk factors for breast cancer, the odds ratio (OR) for a history of diagnostic chest x-rays, excluding those for tuberculosis or pneumonia, was 1.16 (95% confidence interval (CI) = 0.64–2.11) for BRCA1 mutations carriers and 1.22 (95% CI=0.62–2.42) for BRCA2 mutations carriers. The OR was statistically elevated for BRCA2 mutation carriers with 3–5 diagnostic chest x-rays (p = 0.01), but not for those with 6 or more chest x-rays. Few women reported chest fluoroscopy for tuberculosis or chest x-rays for pneumonia; the OR estimates were elevated, but not statistically significant, for BRCA1 mutation carriers.

Conclusions

Our findings do not support a positive association between diagnostic chest x-rays and breast cancer risk before age 50 years for BRCA1 or BRCA2 mutation carriers.

Impact

Given the increasing use of diagnostic imaging involving higher ionizing radiation doses, further studies of genetically predisposed women are warranted.

Introduction

There is extensive epidemiologic evidence that exposure to moderate- and high-dose ionizing radiation, particularly at young ages, is associated with an increase in a woman’s risk of developing breast cancer (1, 2). In contrast, relatively few studies have evaluated the association between low-dose diagnostic chest x-rays and breast cancer risk. Positive associations have been reported for tuberculosis patients monitored with frequent fluoroscopy (3, 4), scoliosis patients evaluated with repeated x-rays of the spine (5), and women with frequent diagnostic chest x-rays before the age of 20 years (6, 7) or 30 years (8), or diagnostic chest x-rays administered before 1960 (8), when radiation doses were likely to be higher than current levels.

There is evidence from some (5–7), but not all (8), studies that breast cancer risk associated with diagnostic chest x-rays is greater for women with a family history of breast cancer. Positive associations with diagnostic chest radiation have also been reported for women carrying a mutation in BRCA1 or BRCA2 (9–12), suggesting that genetically predisposed women could be sensitive to low-dose diagnostic radiation exposure. For mammography, a common source of low-dose radiation, three studies found no significant associations with breast cancer risk for BRCA1 and BRCA2 mutation carriers (12–14).

Since BRCA1 and BRCA2 are involved in the detection and cellular repair of DNA double-strand breaks induced by ionizing radiation (15), it is plausible that BRCA1 and BRCA2 mutation carriers may have reduced ability to repair radiation-induced DNA damage and, therefore, be at increased risk of radiation-induced breast cancer. Women who receive therapeutic radiotherapy for their first breast cancer have an elevated risk for contralateral breast cancer (16) which could be even further increased for those who carry a germline mutation in a gene involved in DNA-damage repair (e.g., ATM, CHEK2, BRCA1, BRCA2) (17–19).

To further study the possible association of low-dose radiation from medical diagnostic procedures, we examined breast cancer risk and diagnostic chest x-rays using self-reported data on exposure from 454 BRCA1 and 273 BRCA2 mutation carriers identified by three large family registries of breast cancer in the USA, Canada and Australia. Because the established association between radiation and breast cancer risk is observed primarily for women exposed to radiation at a young age, we analyzed only mutation carriers aged <50 years.

Materials and Methods

Study sample

A detailed description of the study design and analytic methods has been provided elsewhere (20). Briefly, women carrying a deleterious mutation in BRCA1 or BRCA2 (see below) were identified from the Breast Cancer Family Registry (BCFR) comprised of six registries in the United States (U.S.), Canada, and Australia (21); the Ontario Cancer Genetics Network (OCGN) in Canada; and the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab) in Australia and New Zealand (22). Three registries of the BCFR ascertained families through probands with incident breast cancer who were sampled from population-based cancer registries. All other families were identified through cancer clinics or community outreach efforts. Probands were either affected or unaffected with breast or ovarian cancer and included those with multiple or early-onset cases of breast or ovarian cancer among first- and second-degree relatives or relatives known to carry a mutation in BRCA1 or BRCA2.

In this case-control analysis of mutation carriers, we defined cases as women carrying a deleterious mutation in BRCA1 or BRCA2 who had been diagnosed with a first primary invasive breast cancer, and controls as mutation carriers without a history of breast cancer. We assigned each carrier a reference age, defined for cases as the age at breast cancer diagnosis, and for controls as the age at the earliest of the following events: questionnaire completion, bilateral mastectomy, bilateral oophorectomy, or diagnosis of in situ breast cancer. We restricted the analysis to carriers with a reference age <50 years. To minimize survival bias, we further restricted the analysis to carriers who completed the questionnaire no more than five years after their reference age. Approximately 82% of carriers completed the questionnaire within three years of their reference age. We excluded from the analysis a small number of BRCA1 mutation carriers (two cases and one control) and BRCA2 mutation carriers (three cases and two controls) who reported therapeutic radiation exposures to the chest prior to breast cancer diagnosis (cases) or interview (controls). The final analysis was based on 454 non-Hispanic white BRCA1 mutation carriers (167 cases and 287 controls) and 273 non-Hispanic white BRCA2 mutation carriers (104 cases and 169 controls).

All participants in the BCFR, OCGN, and kConFab provided written informed consent to participate in research programs that were approved by the Institutional Review Board of each center participating in the BCFR, OCGN, and kConFab. This study was approved by the Institutional Review Board of the Stanford University School of Medicine.

Data collection

All study sites used the same structured questionnaire, completed by interview or mail. Information was collected on established and suspected breast cancer risk factors, including chest x-ray examinations (other than mammograms) and radiation treatment to the chest area prior to breast cancer diagnosis for cases or interview for controls. The questionnaire asked about treatment with radiation for selected conditions (i.e., tuberculosis, cancer, acne, mastitis, enlarged thymus, or hemangioma), and other conditions in the chest area, as well as diagnostic x-ray examinations for heart catheterization or scoliosis, or other intensive x-ray examinations of the chest area. When a participant reported “therapeutic chest x-rays for other conditions” or “other intensive x-ray examinations of the chest area”, information was requested on the type of condition. The term “other intensive chest x-rays” was not further defined in the questionnaire. Although the questionnaire listed tuberculosis as a condition for treatment with radiation, we recognize that fluoroscopy was used to follow the progress of lung inflation to normal after induced pneumothorax treatment for tuberculosis; radiation was not used as a treatment for tuberculosis per se. For both therapeutic and diagnostic radiation exposure, information was collected on age at first exposure and total number of exposures. Since we previously found positive associations between breast cancer risk and chest fluoroscopy for tuberculosis and chest x-rays for pneumonia (8), we examined associations with these two exposure categories separately. All other diagnostic chest x-rays (e.g., back or shoulder examinations, upper body bone fractures, routine chest x-rays, and chest x-rays for unspecified indications) were pooled together for the analysis. X-rays from mammograms were not considered, as the questionnaire did not assess a lifetime mammography history.

BRCA1 and BRCA2 mutation testing

BRCA1 and BRCA2 mutation testing was performed for incident breast cancer cases recruited from the three population-based BCFR registries and the youngest breast cancer case for families from clinics. Women of Ashkenazi Jewish ancestry were tested for the three founder mutations. Testing was performed either by complete gene sequencing at Myriad Genetics, Inc. or by one of several other methods: enzymatic mutation detection, two-dimensional gene scanning, chemical cleavage of mismatch, the protein truncation test, single strand conformation polymorphism analysis, heteroduplex analysis and denaturing high-performance liquid chromatography (DHPLC) (23–25). Mutations considered included small insertions and deletions, nonsense mutations, and splice site variants that all resulted in truncated and dysfunctional BRCA1 and BRCA2 proteins. All mutations were confirmed by sequencing. The analysis for this study was restricted to carriers of mutations that were classified as deleterious by applying the criteria used by the Breast Information Core and Myriad Genetics Inc., as described elsewhere (24). When a deleterious mutation was identified, all relatives of the carrier who had provided a DNA sample were subsequently tested for the same mutation.

Statistical analysis

We used unconditional logistic regression implemented in SAS version 9.1 to estimate odds ratios (OR) and 95% confidence intervals (CI). A robust variance estimator was used to account for possible correlation in covariates between family members (26). This approach accommodates the possibility that some carriers were ascertained because of their breast cancer status. Valid inferences for association parameters can be obtained by ignoring other ascertainment issues provided that the exposure-disease OR for ascertained carriers is equal to the corresponding OR for unascertained carriers having the same family history (26). This condition would be violated only if ascertainment modified the association between exposure and breast cancer. All regression models included reference age as a categorical (<40 and 40–49 years) variable and as a continuous variable, dummy variables for country/region (Canada, Australia, Utah, other U.S. sites), family history of breast or ovarian cancer in first-degree relatives (yes, no), and number of full-term pregnancies (0, 1–2, ≥3). Based on our previous finding of increased breast cancer risk associated with chest fluoroscopy for tuberculosis and chest x-rays for pneumonia (8), we estimated breast cancer risk in relation to three categories of diagnostic x-ray exposure: chest fluoroscopy for tuberculosis, chest x-rays for pneumonia, and chest x-rays for other reasons. Women in these exposure categories were compared with a single referent category that included women without a history of therapeutic and diagnostic chest x-rays.

Results

Characteristics of cases and controls are shown in Table 1. Cases were older than controls and fewer cases than controls had a college or university degree. More controls than cases were ascertained from clinic-based sources and had a family history of breast or ovarian cancer which is the result of the ascertainment and BRCA1 and BRCA2 mutation testing protocols (20).

Table 1.

Characteristics of non-Hispanic white BRCA1 and BRCA2 mutation carriers, by case-control status

	BRCA1 mutation carriers				BRCA2 mutation carriers
	Cases (n=167)		Controls (n=287)		Cases (n=104)		Controls (n=169)
	N	%	N	%	N	%	N	%
Reference age (years)
<30	18	11	77	27	8	8	34	20
30–39	73	44	104	36	51	49	57	34
40–49	76	45	106	37	45	43	78	46
Study site
Australia	75	45	117	41	50	48	84	50
Canada	39	23	11	4	27	26	12	7
USA	53	32	159	55	27	26	73	43
Ascertainment
Clinic-based	99	59	271	94	59	57	148	88
Population-based	68	41	16	6	45	43	21	12
Education
Less than college or university	45	27	51	18	18	17	39	23
Some college or university	67	40	124	43	52	50	66	39
College or university degree	54	33	112	39	31	30	64	38
Unknown	0	0	0	0	3	3	0	0
Family history of breast or ovarian cancer a
Yes	102	61	218	76	56	54	119	70
No	65	39	69	24	48	46	50	30
Full-term pregnancies
0	45	27	97	34	22	21	37	22
1–2	85	51	111	39	48	46	78	46
≥3	37	22	78	27	34	33	54	32

^ain first-degree relatives

For BRCA1 mutation carriers, a history of diagnostic chest x-rays was not associated with breast cancer risk (OR=1.31, 95% CI=0.75–2.30) (Table 2). There was no evidence of increased risk associated with diagnostic chest x-rays (OR=1.16, 95% CI=0.64–2.11), excluding those for pneumonia or chest fluoroscopy. Elevated, but statistically not significant, ORs were associated with a history of chest fluoroscopy for tuberculosis (OR=2.58, 95% CI=0.22–30) and chest x-rays for pneumonia (OR=4.54, 95% CI=0.53–30). For other chest x-rays (excluding those for pneumonia or chest fluoroscopy), risk did not vary by age or year at first chest x-ray or total number of chest x-rays.

Table 2.

Diagnostic chest x-rays and breast cancer risk for non-Hispanic White women, by BRCA1 and BRCA2 mutation status

	BRCA1 mutation carriers				BRCA2 mutation carriers
	Cases N=167	Controls N=287	Multivariate adjusted OR (95% CI) a		Cases N=104	Controls N=169	Multivariate adjusted OR (95% CI) a
History of diagnostic chest x-rays
No chest x-rays	125	246	1.0		76	133	1.0
One or more chest x-rays	42	41	1.31	0.75–2.30	28	36	1.13	0.59–2.18
Chest fluoroscopy for tuberculosis	3	1	2.58	0.22–30	2	2	0.93	0.11–7.89
Chest x-rays for pneumonia	3	2	4.54	0.53–39	2	2	0.33	0.02–5.63
Other diagnostic chest x-rays	36	38	1.16	0.64–2.11	24	32	1.22	0.62–2.42
Other diagnostic chest x-rays b
Age at first chest x-ray (years)
No chest x-rays	125	246	1.0		76	133	1.0
<20	10	22	0.57	0.22–1.48	9	10	1.55	0.54–4.47
≥20	21	14	1.69	0.76–3.76	11	17	1.06	0.43–2.60
Unknown	5	2	2.58	0.42–15.8	4	5	1.12	0.24–5.26
Year of first chest x-ray
No chest x-rays	125	246	1.0		76	133	1.0
Before 1980	16	17	1.14	0.48–2.70	10	6	2.18	0.69–6.88
1980 or after	15	19	1.01	0.44–2.29	10	21	0.90	0.37–2.19
Unknown	5	2	2.62	0.43–16.0	4	5	1.10	0.24–5.12
Number of chest x-rays
No chest x-rays	125	246	1.0		76	133	1.0
1–2	11	16	0.84	0.33–2.13	7	15	0.80	0.28–2.28
3–5	8	6	1.22	0.35–4.21	9	2	10.63	1.93–58
≥6	6	7	1.20	0.37–3.96	3	3	0.89	0.15–5.49
Unknown	11	9	1.75	0.57–5.35	5	12	0.62	0.18–2.17

^aOdds ratio (OR) and 95% confidence interval (CI), adjusted for age, study site, family history of breast or ovarian cancer in first-degree relatives, and number of full-term pregnancies.

^bExcluding individuals with chest x-rays fluoroscopy for tuberculosis or chest x-rays for pneumonia.

Similarly, for BRCA2 mutation carriers, there was no evidence of increased breast cancer risk associated with a history of diagnostic chest x-rays (OR=1.13, 95% CI=0.59–2.18) (Table 2). Subgroup analyses showed an elevated risk only for carriers with 3–5 chest x-rays (OR=10.6, 95% CI=1.93–58), excluding those for pneumonia or chest fluoroscopy.

Discussion

The results from the present study suggest that for BRCA1 and BRCA2 mutation carriers aged <50 years, there is no association between diagnostic chest x-rays and breast cancer risk, neither for exposure at any age, nor for exposure before age 20 years when radiosensitivity is highest. For BRCA2 mutation carriers, our finding of a large OR estimate associated with 3–5 diagnostic x-rays, bounded by a wide confidence interval, is likely due to chance, given the lack of association with ≥6 x-rays.

Few prior studies have examined diagnostic x-ray exposure and breast cancer risk for BRCA1 and BRCA2 mutation carriers and, in contrast to our findings, strong associations have been reported by some of the European studies (9, 11, 12) (Table 3). There was, however, some overlap in mutation carriers between the three European studies (9, 11, 12); the analysis by Andrieu et al. (9) included 319 French mutation carriers from the study by Lecarpentier (11), and 21% of mutation carriers included in the analysis by Pijpe et al. (12) were also included in the study by Andrieu et al. (9). In the incident cohort analysis by Andrieu et al. (9) of 969 mostly European BRCA1 and BRCA2 mutation carriers, a history of diagnostic chest x-rays (excluding mammograms) was associated with increased breast cancer risk (HR=1.75, 95% CI=1.1–2.8). For women aged ≤40 years, risk was increased more than two-fold (HR=2.75, 95% CI=1.4–5.3). Similarly, in the French study of 990 BRCA1 and BRCA2 mutation carriers, breast cancer risk associated with a history of diagnostic chest x-rays (excluding mammograms) was increased both for BRCA1 (HR=4.12, 95% CI=1.82–9.35) and BRCA2 (HR=5.43, 95% CI=1.36–21.7) mutation carriers (11). The largest study to date by Pijpe et al. (12) assessed associations with several categories of diagnostic radiation exposure, including fluoroscopy, conventional radiography (x-rays) of chest or shoulders, mammography, computed tomography of chest or shoulders, and other diagnostic procedures (e.g., bone scans). Consistent with our findings, there were no statistically significant associations with a history of diagnostic chest x-rays (HR=1.38, 95% CI=0.87–2.20) or chest x-rays before age 20 years (HR=1.29, 95% CI=0.84–1.98) for BRCA1 and BRCA2 mutation carriers combined. In that study, significant associations with diagnostic radiation exposure emerged only when all types of exposures (fluoroscopy, x-rays, mammography, other diagnostic procedures) before age 30 years were considered jointly (HR=1.90, 95% CI=1.20–3.00). Lastly, a Polish study of breast cancer patients diagnosed at age ≤50 years compared 138 affected BRCA1 mutation carriers with 158 affected non-carriers; affected carriers were more likely to report a history of chest x-rays before age 30 years than affected non-carriers (OR=1.8, 95% 1.2–2.9) (10).

Table 3.

Summary of published studies on diagnostic chest x-rays and breast cancer risk for BRCA1 and BRCA2 mutation carriers

	Andrieu et al. 2006 (9)	Lecarpentier et al. 2011 (11)	Pijpe et al. 2012 (12)	Gronwald et al. 2008 (10)	Current study
Study	IBCCS Cohort (2/3 of carriers are from GENEPSO, EMBRACE, HEBON)	GENEPSO	GENE-RAD-RISK Cohort (carriers from GENEPSO, EMBRACE, HEBON)	Study of early-onset breast cancer	BCFR, OCGN, kConFab
Country	13 European countries a; Quebec Canada	France	France, UK, Netherlands	Poland	USA, Canada, Australia, New Zealand
Ascertainment of BRCA1 and BRCA2 mutation carriers	Family cancer clinics or previous participation in research family studies	Family cancer clinics	Family cancer clinics and clinical genetic centers	Unselected breast cancer cases from 18 hospitals	Participation in research family studies
Number of affected/unaffected BRCA1 and BRCA2 mutation carriers included in analysis	295/674 b	379/611 c	174/948 b	138 affected BRCA1 carriers 158 affected non-carriers	271/456
Age (years)	≥18	≥18	≥18	30–50	≤50
Birth cohort	<1940 to ≥1960	<1950 to ≥1970	<1955 to >1968	1948–1972	1940 to ≥1970
Data collection	1997–2002 Mailed questionnaire	2000–2010 Mailed questionnaire	2006–2009 Mailed questionnaire	1996–2002 Mailed questionnaire	1995–2003 Mailed questionnaire or interview
Assessment of diagnostic chest x-rays	Chest x-rays	Chest x-rays	Conventional radiography of chest or shoulders	Chest x-rays before age 30 y	Chest x-rays for heart catherization, scoliosis, other intensive chest x-rays
	Excluding mammograms	Excluding mammograms	Excluding fluoroscopy or mammograms		Excluding mammograms, chest fluoroscopy for tuberculosis or chest x-rays for pneumonia
	Number of x-rays at ages <20 y, ≥20 y	Number of x-rays at ages <20 y, ≥20 y	Age at first x-rays, number of x-rays at ages <20 y, 20–29 y, 30–39 y, age at last x-rays	Age at first x-ray, total number of x-rays	Age at first x-rays, total number of x-rays
Frequency of chest x-rays
Affected carriers	70%	96%	51% d	53%	22% d
Unaffected carriers	50%	76%	45% d		15% d
Frequency of chest x-rays at age <20 y
Affected carriers	66%	88%	31%	23%	7%
Unaffected carriers				15% f	7%
Association with chest x-rays (ever, never) d
BRCA1 carriers	HR=1.91 (1.1–3.3) b	HR=4.12 (1.82–9.35) c		OR=1.8 (1.2–2.9) g	OR=1.16 (0.64–2.11) d
BRCA2 carriers	HR=1.71 (0.4–8.2) b	HR=5.43 (1.36–21.7) c			OR=1.22 (0.62–2.42) d
All carriers	HR=1.75 (1.1–2.8) b	HR=4.29 (2.09–8.81) c	HR=1.38 (0.87–2.20)
Association with first chest x-rays (ever, never) at age <20 y a
BRCA1 carriers				OR=1.7 (0.9–3.0) g	OR=0.57 (0.22–1.48) d
BRCA2 carriers					OR=1.55 (0.54–4.47) d
All carriers	HR=5.21 (1.6–17.5) b,h	HR=4.16 (2.03–8.56) c	HR=1.29 (0.84–1.98) b,d

^aUnited Kingdom, Ireland, Netherlands, France, Spain, Italy, Austria, Belgium, Germany, Hungary, Iceland, Denmark, Sweden.

^bMain analysis was based on cohort comprised of BRCA1 and BRCA2 mutation carriers who were diagnosed with breast cancer or who were censored within the 5 years before questionnaire completion.

^cMain analysis was based on cohort comprised of one woman per family.

^dExcludes chest fluoroscopy for tuberculosis.

^eHazard ratio (HR) and 95% confidence interval; or odds ratio (OR) and 95% confidence interval.

^fAmong affected non-carriers.

^gOdds of having x-ray exposure for carriers vs. non-carriers.

^hChest x-rays (ever, never) at age <20 y only.

Our findings of a relatively large OR estimate associated with chest fluoroscopy for tuberculosis is in agreement with the study by Pijpe et al. (12) that found a two-fold increased risk for exposure before age 20 years, but in both studies the associations were based on small numbers of exposed mutation carriers and were not statistically significant. Chest fluoroscopy for tuberculosis has also been associated with increased breast cancer risk (3, 8) and mortality (4) in the general population. It is uncertain whether in the other European studies (9–11) reports of chest x-rays included fluoroscopy for tuberculosis. The inclusion of fluoroscopy could have contributed to the positive associations with chest x-rays, particularly for exposures before age 20 years. In our study, we asked about diagnostic x-ray exposure for heart catheterization and for the monitoring of scoliosis, which has been associated with increased breast cancer risk (5) and mortality (27) in the U.S. Scoliosis Cohort Study. For other intensive x-rays, we requested the reason for the diagnostic procedure. Although our questionnaire did not ask specifically about chest fluoroscopy, some women reported such exposure under “other intensive diagnostic x-rays” or in the questionnaire section on therapeutic radiation.

The most striking difference between the European studies and ours is the prevalence of self-reported diagnostic x-rays (Table 3). For unaffected carriers, the proportion of women who reported a history of diagnostic chest x-rays ranged from 15% (not including those for pneumonia or chest fluoroscopy for tuberculosis) in our study, to 45% (not including fluoroscopy) in the study by Pijpe et al. (12), 50% in the study by Andrieu et al. (9), and 76% in the study by Lecarpentier et al. (11). Differences in the prevalence of reported chest x-rays were particularly pronounced for exposures before age 20 years. For affected carriers, proportions ranged from 7% in our study, to 23% in the Polish study (10), 31% in the study by Pijpe et al. (12), 66% in the study by Andrieu et al. (9), and 88% in the study by Lecarpentier (11). Large differences were also seen in the prevalence of fluoroscopy; a positive history was reported by 2% of affected mutation carriers in our study, compared with 15% in the European study by Andrieu et al. (12).

Differences in the frequency of self-reported diagnostic chest radiation could be due to differences between studies in the wording of questions and/or the inclusion of specific diagnostic procedures, differences between countries in the practice of administering diagnostic x-rays, or differences between studies in the age distribution, or birth cohorts, of the mutation carriers. The frequency of medical x-rays has been shown to vary between countries (28). Chest fluoroscopy, for example, has been reported to be more common in Sweden than in the U.S. (29), and in the Netherlands, mass population screening for tuberculosis was performed in young people from 1940–1960 (12). Analytic differences between the European studies may have also contributed to differences in results. As commented by Pijpe et al. (12), the analysis by Andrieu et al. (9) assessed lifetime x-rays, including exposure after diagnosis of breast cancer, potentially biasing associations away from the null.

Since the frequency and spectrum of mutations in BRCA1 and BRCA2 vary by race/ethnicity (30, 31), we limited our analysis to non-Hispanic white mutation carriers. Breast cancer risk in mutation carriers, however, appears to vary by mutation position (32, 33). It is not known whether radiation sensitivity varies by mutation type and position. Lecarpentier et al. (11) found no variation in breast cancer risk associated with chest x-rays by mutation position in BRCA1 or BRCA2. Larger studies will be needed to assess whether the differences in associations between our study and the European studies are due to differences in mutation types and radiosensitivity.

Several study limitations need to be considered when interpreting our results. As in previous studies (9–12), our exposure assessment relied on self-report. We, therefore, cannot rule out the possibility of inaccurate recall, especially of diagnostic procedures in the distant past. In the few studies conducted in the U.S. (29, 34) and Sweden (29, 35) that compared self-reported diagnostic x-rays and other diagnostic imaging against medical records, reporting errors tended to be non-differential by disease status (29, 34, 36), although in one of the Swedish studies there was evidence of differential recall bias for those aged under 50 years (35). A study from the Netherlands (36) that assessed the reliability of self-reported chest x-rays among BRCA1 and BRCA2 mutation carriers, reported the agreement between baseline and follow-up reports was non-differential by disease status. Non-differential exposure misclassification would bias risk estimates towards the null and might have reduced the possibility of finding a true association in our study. It is also possible that we failed to find statistically significant associations with diagnostic chest x-rays, especially for chest fluoroscopy and x-rays for pneumonia, due to insufficient power stemming from limited sample sizes. Our risk estimates have wide confidence intervals and are, therefore, imprecise. Future studies of BRCA1 and BRCA2 mutation carriers would benefit from improved exposure assessment, including queries about all types of diagnostic imaging procedures in the chest area, including mammograms which we did not assess in the current study.

Strengths of this study include use of the same questionnaire by the three family registry studies to assess therapeutic and diagnostic chest x-rays, which allowed us to identify unexposed carriers as the referent, and the focus on younger mutation carriers who need better guidelines for diagnostic procedures involving ionizing radiation at a young age. To minimize potential survival bias, we limited the affected mutation carriers to those who completed the questionnaire within 5 years of diagnosis. Our results remained unchanged when we further restricted the affected mutation carriers to those who completed the questionnaire within 3 years of diagnosis (data not shown).

Future studies should include larger numbers of BRCA1 and BRCA2 mutation carriers, and obtain detailed information on diagnostic imaging of the chest, including type and number of procedures, age at first exposure, and indications that required diagnostic procedures to the chest. Ideally, such reports would be verified by medical records to minimize any recall bias. However, given that ionizing radiation exposure at a young age (e.g., before age 20 years) is the most relevant window of susceptibility for radiation-induced breast cancer, retrospective verification may be very difficult, if not impossible. Study designs that include prospective breast cancer cases in a mutation carrier cohort providing baseline information on low-dose radiation exposure prior to diagnosis would avoid differential recall bias by case status.

Conclusions

Our findings do not support a positive association between diagnostic chest x-rays and breast cancer risk before age 50 years for BRCA1 and BRCA2 mutation carriers. Nevertheless, continued surveillance of the possible effects of diagnostic radiation exposure on breast cancer risk is warranted for these women, given the widespread and increasing use of diagnostic imaging involving ionizing radiation. Special attention might need to be paid to computed tomography, an imaging technology that is being used with increasing frequency both for children and adults and delivers much larger doses of ionizing radiation than conventional chest x-rays (37–39).