Radiation Epidemiology Study Research Articles

International symposium on the natural radiation exposures and low-dose radiation epidemiological studies

International symposium on the natural radiation exposures and low-dose radiation epidemiological studies

New insights into the risk of breast cancer in childhood cancer survivors treated with chest radiation: A report from the Childhood Cancer Survivor Study (CCSS) and the Women's Environmental Cancer and Radiation Epidemiology(WECARE) Study.

CRA9513 Background: The risk of breast cancer (BC) by age 50 among women treated for childhood cancer with chest radiation therapy (RT) and how this risk compares with that of BRCA1 and BRCA2 (BRCA1/2) mutation carriers is unknown. Methods: We evaluated the risk of BC in a cohort of 1268 female 5-yr childhood cancer survivors treated with chest RT and estimated the cumulative incidence of BC non-parametrically treating death as a competing risk. The cumulative incidence of BC in BRCA1/2 mutation carriers was estimated with the kin-cohort method using data from 4570 female first-degree relatives of women diagnosed with unilateral BC (probands) participating in the WECARE Study. Absolute Excess Risks (AERs) were estimated using population-based data from the SEER program. Results: With a median follow-up of 26 yrs (range 5-39) for the CCSS cohort, 175 women were diagnosed with BC at a median age of 38 yrs (range 24-53) and a median latency of 23 yrs (range 7-38); the overall cumulative incidence of BC by age 50 was 24% (95% confidence interval [CI] 20-28%) and among Hodgkin lymphoma survivors was 30% (95% CI 25-35%). In comparison, among first-degree relatives of WECARE Study probands 324 were diagnosed with BC (median age at diagnosis, 55 yrs (range 26-90)). The estimated cumulative incidence by age 50 was 31% (95% CI 16-47%) and 10% (95% CI 2-23%) in carriers of BRCA1 and BRCA2 mutations, respectively. The population cumulative incidence of BC is 4% by age 50. Among the childhood cancer survivors, AERs for BCs diagnosed per 10,000 person-years of observation were respectively 34 (95% CI 18-52), 27 (95% CI 11-45), and 95 (95% CI 78-112) among women treated with 10-19 Gy (23%), 20-29 Gy (17%), and 30+ Gy (56%) of chest RT. Conclusions: Women treated for childhood cancer with chest RT have a substantial risk of BC comparable to BRCA1/2 mutation carriers and considerably greater than that of the general population. Women treated with 10-19 Gy RT had an increased excess risk warranting consideration of breast cancer surveillance strategies similar to the current recommendations for women treated with > 20 Gy.

New insights into the risk of breast cancer in childhood cancer survivors treated with chest radiation: A report from the Childhood Cancer Survivor Study (CCSS) and the Women's Environmental Cancer and Radiation Epidemiology(WECARE) Study.

CRA9513 The full, final text of this abstract will be available at abstract.asco.org at 12:01 AM (EDT) on Monday, June 4, 2012, and in the Annual Meeting Proceedings online supplement to the June 20, 2012, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.

Reproductive Status at First Diagnosis Influences Risk of Radiation-Induced Second Primary Contralateral Breast Cancer in the WECARE Study

Our study examined whether reproductive and hormonal factors before, at the time of, or after radiation treatment for a first primary breast cancer modify the risk of radiation-induced second primary breast cancer. The Women's Environmental, Cancer and Radiation Epidemiology (WECARE) Study is a multicenter, population-based study of 708 women (cases) with asynchronous contralateral breast cancer (CBC) and 1399 women (controls) with unilateral breast cancer. Radiotherapy (RT) records, coupled with anthropomorphic phantom simulations, were used to estimate quadrant-specific radiation dose to the contralateral breast for each patient. Rate ratios (RR) and 95% confidence intervals (CI) were computed to assess the relationship between reproductive factors and risk of CBC. Women who were nulliparous at diagnosis and exposed to ≥1 Gy to the contralateral breast had a greater risk for CBC than did matched unexposed nulliparous women (RR=2.2; 95% CI, 1.2-4.0). No increased risk was seen in RT-exposed parous women (RR=1.1; 95% CI, 0.8-1.4). Women treated with RT who later became pregnant (8 cases and 9 controls) had a greater risk for CBC (RR=6.0; 95% CI, 1.3-28.4) than unexposed women (4 cases and 7 controls) who also became pregnant. The association of radiation with risk of CBC did not vary by number of pregnancies, history of breastfeeding, or menopausal status at the time of first breast cancer diagnosis. Nulliparous women treated with RT were at an increased risk for CBC. Although based on small numbers, women who become pregnant after first diagnosis also seem to be at an increased risk for radiation-induced CBC.

Lessons from Chernobyl and prognosis for Fukushima: radiological consequences

The following are considered: results of large-scale radiation epidemiological studies of thehealth effects of the Chernobyl accident, radiation risks for emergency workers and theaffected population; and verification of ICRP risk models taking into account data on theChernobyl accident and preliminary prognostic estimates of potential radiologicalconsequences of the Fukushima disaster.

Rare germline mutations inPALB2and breast cancer risk: A population-based study

Germline mutations in the PALB2 gene are associated with an increased risk of developing breast cancer but little is known about the frequencies of rare variants in PALB2 and the nature of the variants that influence risk. We selected participants recruited to the Women's Environment, Cancer, and Radiation Epidemiology (WECARE) Study and screened lymphocyte DNA from cases with contralateral breast cancer (n = 559) and matched controls with unilateral breast cancer (n = 565) for PALB2 mutations. Five pathogenic PALB2 mutations were identified among the cases (0.9%) versus none among the controls (P = 0.04). The first-degree female relatives of these five carriers demonstrated significantly higher incidence of breast cancer than relatives of noncarrier cases, indicating that pathogenic PALB2 mutations confer an estimated 5.3-fold increase in risk (95% CI: 1.8-13.2). The frequency of rare (<1% MAF) missense mutations was similar in both groups (23 vs. 21). Our findings confirm in a population-based study setting of women with breast cancer the strong risk associated with truncating mutations in PALB2 that has been reported in family studies. Conversely, there is no evidence from this study that rare PALB2 missense mutations strongly influence breast cancer risk.

Single nucleotide polymorphisms associated with risk for contralateral breast cancer in the Women's Environment, Cancer, and Radiation Epidemiology (WECARE) Study

IntroductionGenome-wide association studies, focusing primarily on unilateral breast cancer, have identified single nucleotide polymorphisms (SNPs) in a number of genomic regions that have alleles associated with a significantly increased risk of breast cancer. In the current study we evaluate the contributions of these previously identified regions to the risk of developing contralateral breast cancer. The most strongly disease-associated SNPs from prior studies were tested for association with contralateral breast cancer. A subset of these SNPs, selected upon their main effects on contralateral breast cancer risk was further evaluated for interaction with treatment modalities and estrogen receptor (ER) status.MethodsWe genotyped 21 SNPs in 708 women with contralateral breast cancer and 1394 women with unilateral breast cancer who serve as the cases and controls in the Women's Environment, Cancer and Radiation Epidemiology (WECARE) Study. Records of treatment and ER status were available for most of WECARE Study participants. Associations of SNP genotypes and risk for contralateral breast cancer were calculated with multivariable adjusted conditional logistic regression methods.ResultsMultiple SNPs in the FGFR2 locus were significantly associated with contralateral breast cancer, including rs1219648 (per allele rate ratio (RR) = 1.25, 95%CI = 1.08-1.45). Statistically significant associations with contralateral breast cancer were also observed at rs7313833, near the PTHLH gene (per allele RR = 1.26, 95%CI = 1.08-1.47), rs13387042 (2q35) (per allele RR = 1.19, 95%CI = 1.02-1.37), rs13281615 (8q24) (per allele RR = 1.21, 95%CI = 1.04-1.40), and rs11235127 near TMEM135 (per allele RR = 1.26, 95%CI = 1.04-1.53). The A allele of rs13387042 (2q35) was significantly associated with contralateral breast cancer in ER negative first tumors while the A allele of rs11235127 (near TMEM135) was significantly associated with contralateral breast cancer in ER positive first tumors. Although some SNP genotypes appeared to modify contralateral breast cancer risk with respect to tamoxifen treatment or particular radiation doses, trend tests for such effects were not significant.ConclusionsOur results indicate that some common risk variants associated with primary breast cancer also increase risk for contralateral breast cancer, and that these risks vary with the ER status of the first tumor.

Abstract B54: Reproductive status at first diagnosis influences risk of radiation-induced second primary contralateral breast cancer in The WECARE Study

Abstract The breast undergoes changes in composition, function and hormonal milieu during puberty, pregnancy, lactation and postmenopausal involution. These changes may influence the susceptibility of the breast to carcinogens, including exposure to ionizing radiation. The Women's Environmental, Cancer and Radiation Epidemiology (WECARE) Study is a multi-center, population-based, case-control study of 708 women (cases) with asynchronous contralateral breast cancer (CBC) and 1,399 women (controls) with unilateral breast cancer (UBC). Radiation therapy (RT) records were used to reconstruct the radiation dose to the location in the contralateral breast where the second cancer arose (or to the equivalent breast location for UBC controls). Rate ratios (RR) and 95% confidence intervals (CI) were computed to assess the relationship between reproductive status at first breast cancer diagnosis, RT and risk of CBC, adjusting for known breast cancer risk factors: age at (first) diagnosis, menopausal status/age at menopause at first diagnosis, age at menarche, number of full-term pregnancies, first degree family history of breast cancer, histology and stage of first primary breast cancer, and treatment (chemotherapy/hormonal therapy). Women who were nulliparous at first diagnosis and exposed to ≥1 gray (Gy) to the contralateral breast, had a higher risk of CBC than unexposed nulliparous women (RR=2.2, 95% CI 1.2–4.0). An increased risk was not seen in RT exposed parous women (RR=1.1, 95% CI 0.8–1.4). Women treated with RT who later became pregnant had a greater risk of CBC compared with unexposed women who also became pregnant (RR=6.0, 95% CI 1.3, 28.4), though these results were based on small numbers. The effect of radiation on risk of CBC did not vary by number of pregnancies, history of breast feeding or menopausal status at the time of first breast cancer diagnosis. These results suggest that RT may be associated with an increased risk of developing a second breast cancer in nulliparous but not parous women. Women who become pregnant after first breast cancer diagnosis may also be at an increased risk of CBC. It is possible that RT could be the initiating event, leading to preneoplastic cellular changes that are then promoted by the hormonal changes of a subsequent pregnancy. Citation Information: Cancer Prev Res 2011;4(10 Suppl):B54.

Variants in activators and downstream targets of ATM, radiation exposure, and contralateral breast cancer risk in the WECARE study

Ionizing radiation (IR) is a breast carcinogen that induces DNA double-strand breaks (DSBs), and variation in genes involved in the DNA DSB response has been implicated in radiation-induced breast cancer. The Women's Environmental, Cancer, and Radiation Epidemiology (WECARE) study is a population-based study of cases with contralateral breast cancer (CBC) and matched controls with unilateral breast cancer. The location-specific radiation dose received by the contralateral breast was estimated from radiotherapy records and mathematical models. One hundred fifty-two SNPs in six genes (CHEK2, MRE11A, MDC1, NBN, RAD50, TP53BP1) involved in the DNA DSBs response were genotyped. No variants or haplotypes were associated with CBC risk (649 cases and 1,284 controls) and no variants were found to interact with radiation dose. Carriers of a RAD50 haplotype exposed to ≥1 gray (Gy) had an increased risk of CBC compared with unexposed carriers (Rate ratios [RR] = 4.31 [95% confidence intervals [CI] 1.93-9.62]); with an excess relative risk (ERR) per Gy = 2.13 [95% CI 0.61-5.33]). Although the results of this study were largely null, carriers of a haplotype in RAD50 treated with radiation had a greater CBC risk than unexposed carriers. This suggests that carriers of this haplotype may be susceptible to the DNA-damaging effects of radiation therapy associated with radiation-induced breast cancer.

Body mass index and risk of second primary breast cancer: The WECARE Study

The identification of potentially modifiable risk factors, such as body size, could allow for interventions that could help reduce the burden of contralateral breast cancer (CBC) among breast cancer survivors. Studies examining the relationship between body mass index (BMI) and CBC have yielded mixed results. From the population-based, case-control, Women's Environmental, Cancer and Radiation Epidemiology (WECARE) Study, we included 511 women with CBC (cases) and 999 women with unilateral breast cancer (controls) who had never used postmenopausal hormone therapy. Rate ratios (RR) and 95% confidence intervals (CI) were used to assess the relationship between BMI and CBC risk. No associations between BMI at first diagnosis or weight-change between first diagnosis and date of CBC diagnosis (or corresponding date in matched controls) and CBC risk were seen. However, obese (BMI ≥ 30 kg/m(2)) postmenopausal women with estrogen receptor (ER)-negative first primary tumors (n = 12 cases and 9 controls) were at an increased risk of CBC compared with normal weight women (BMI < 25 kg/m(2)) (n = 43 cases and 98 controls) (RR = 5.64 (95% CI 1.76, 18.1)). No association between BMI and CBC risk was seen in premenopausal or postmenopausal women with ER-positive first primaries. Overall, BMI is not associated with CBC risk in this population of young breast cancer survivors. Our finding of an over five-fold higher risk of CBC in a small subgroup of obese postmenopausal women with an ER-negative first primary breast cancer is based on limited numbers and requires confirmation in a larger study.

Abstract B127: Family history of breast cancer and risk of contralateral breast cancer

Abstract Purpose: Family history of breast cancer increases a woman's risk of developing a first primary breast cancer. A meta-analysis of case-control studies of first primary breast cancer reported an increased risk associated with having an affected first-degree relative (OR=2.1, 95% CI=2.0–2.2), and the risk was even greater when subject and relative were diagnosed before age 50 (OR=3.3, 95% CI=2.8–3.9) (Int J Ca 1997;71:800–9). In this study, we examined family history of breast cancer as a risk factor for developing asynchronous contralateral breast cancer (CBC) and compared these risks to those from the aforementioned meta-analysis. Methods: The Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study is a case-control study including women from five population-based cancer registries: four in the US and one in Denmark. The 708 cases in this study were women with CBC and the 1399 individually matched controls were women with unilateral breast cancer (UBC). All participants were initially diagnosed between January 1985 and December 2000 at age 54 years or younger, and were queried about family history of breast cancer among female first- and second-degree relatives. Multivariable-adjusted rate ratios (RR) and corresponding 95% confidence intervals (CI) were calculated using conditional logistic regression. Results: Compared with women who reported no affected relatives, women with at least one first-degree relative with breast cancer were at increased risk of developing CBC (RR=2.1, 95% CI=1.6–2.7); the risk was greater when more than one relative was affected (RR=2.6, 95% CI=1.5–4.6), and was nearly 4-fold (RR=3.9, 95% CI=2.3–6.4) for women having a relative diagnosed with CBC. The risk of CBC was 3.1 (95% CI=1.8–5.3) when both relative and subject were diagnosed before age 45. When the relative was diagnosed before age 45, regardless of subject age, the risk of CBC was 2.6 (95% CI=1.7–4.1). Similarly, when the subject was diagnosed before age 45, regardless of relative's age, the risk of CBC was 2.5 (95% CI=1.7–3.6). Conclusions: The risk of developing CBC is increased among women with a family history of breast cancer, and this risk is significantly greater among those with an affected relative with bilateral cancer, having more than one affected relative, and having relatives affected at young ages. Our results comparing CBC cases to UBC controls were similar to studies where UBC cases are compared to population controls. Citation Information: Cancer Prev Res 2010;3(1 Suppl):B127.

Radiation Exposure, the ATM Gene, and Contralateral Breast Cancer in the Women's Environmental Cancer and Radiation Epidemiology Study

Ionizing radiation is a known mutagen and an established breast carcinogen. The ATM gene is a key regulator of cellular responses to the DNA damage induced by ionizing radiation. We investigated whether genetic variants in ATM play a clinically significant role in radiation-induced contralateral breast cancer in women. The Women's Environmental, Cancer, and Radiation Epidemiology Study is an international population-based case-control study nested within a cohort of 52,536 survivors of unilateral breast cancer diagnosed between 1985 and 2000. The 708 case subjects were women with contralateral breast cancer, and the 1397 control subjects were women with unilateral breast cancer matched to the case subjects on age, follow-up time, registry reporting region, and race and/or ethnicity. All women were interviewed and underwent full mutation screening of the entire ATM gene. Complete medical treatment history information was collected, and for all women who received radiotherapy, the radiation dose to the contralateral breast was reconstructed using radiotherapy records and radiation measurements. Rate ratios (RRs) and corresponding 95% confidence intervals (CIs) were estimated by using multivariable conditional logistic regression. All P values are two-sided. Among women who carried a rare ATM missense variant (ie, one carried by <1% of the study participants) that was predicted to be deleterious, those who were exposed to radiation (mean radiation exposure = 1.2 Gy, SD = 0.7) had a statistically significantly higher risk of contralateral breast cancer compared with unexposed women who carried the wild-type genotype (0.01-0.99 Gy: RR = 2.8, 95% CI = 1.2 to 6.5; > or =1.0 Gy: RR = 3.3, 95% CI = 1.4 to 8.0) or compared with unexposed women who carried the same predicted deleterious missense variant (0.01-0.99 Gy: RR = 5.3, 95% CI = 1.6 to 17.3; > or =1.0 Gy: RR = 5.8, 95% CI = 1.8 to 19.0; P(trend) = .044). Women who carry rare deleterious ATM missense variants and who are treated with radiation may have an elevated risk of developing contralateral breast cancer. However, the rarity of these deleterious missense variants in human populations implies that ATM mutations could account for only a small portion of second primary breast cancers.

Hybrid computational phantoms for medical dose reconstruction

As outlined in NCRP Report No. 160 of the US National Council on Radiation Protection and Measurements (NCRP), the average value of the effective dose to exposed individuals in the United States has increased by a factor of 1.7 over the time period 1982-2006, with the contribution of medical exposures correspondingly increasing by a factor of 5.7. At present, medical contributors to effective dose include computed tomography (50% of total medical exposure), nuclear medicine (25%), interventional fluoroscopy (15%), and conventional radiography and diagnostic fluoroscopy (10%). An increased awareness of medical exposures has led to a gradual shift in the focus of radiation epidemiological studies from traditional occupational and environmental exposures to those focusing on cohorts of medical patients exposed to both diagnostic and therapeutic sources. The assignment of organ doses to patients in either a retrospective or a prospective study has increasingly relied on the use of computational anatomic phantoms. In this paper, we review the various methods and approaches used to construct patient models to include anthropometric databases, cadaver imaging, prospective volunteer imaging studies, and retrospective image reviews. Phantom format types--stylized, voxel, and hybrid--as well as phantom morphometric categories--reference, patient-dependent, and patient-specific--are next defined and discussed. Specific emphasis is given to hybrid phantoms-those defined through the use of combinations of polygon mesh and non-uniform rational B-spline (NURBS) surfaces. The concept of a patient-dependent phantom is reviewed, in which phantoms of non-50th percentile heights and weights are designed from population-based morphometric databases and provided as a larger library of phantoms for patient matching and lookup of refined values of organ dose coefficients and/or radionuclide S values. We close with two brief examples of the use of hybrid phantoms in medical dose reconstruction--diagnostic nuclear medicine for pediatric subjects and interventional fluoroscopy for adult patients.

Alcohol Intake and Cigarette Smoking and Risk of a Contralateral Breast Cancer: The Women's Environmental Cancer and Radiation Epidemiology Study

Women with primary breast cancer are at increased risk of developing second primary breast cancer. Few studies have evaluated risk factors for the development of asynchronous contralateral breast cancer in women with breast cancer. In the Women's Environmental Cancer and Radiation Epidemiology Study (1985-2001), the roles of alcohol and smoking were examined in 708 women with asynchronous contralateral breast cancer (cases) compared with 1,399 women with unilateral breast cancer (controls). Cases and controls aged less than 55 years at first breast cancer diagnosis were identified from 5 population-based cancer registries in the United States and Denmark. Controls were matched to cases on birth year, diagnosis year, registry region, and race and countermatched on radiation treatment. Risk factor information was collected by telephone interview. Rate ratios and 95% confidence intervals were estimated by using conditional logistic regression. Ever regular drinking was associated with an increased risk of asynchronous contralateral breast cancer (rate ratio = 1.3, 95% confidence interval: 1.0, 1.6), and the risk increased with increasing duration (P = 0.03). Smoking was not related to asynchronous contralateral breast cancer. In this, the largest study of asynchronous contralateral breast cancer to date, alcohol is a risk factor for the disease, as it is for a first primary breast cancer.

Exposure assessment: implications for epidemiological studies of ionizing radiation

Quantitative estimates of ionizing radiation exposure are often available for use in epidemiological studies. However, depending on the context, the quality of the exposure estimates can vary. For example, the estimates may be specific to individuals in the study or generic values averaged over populations; unavailable for some of the potential study subjects or vary in their form between individuals; based on contemporary measurements or assessed retrospectively; based on measurements alone, on surrogate measures of exposure, or on an exposure assessment model; or, as is often the case, cover one source of radiation exposure rather than all of them. Various ways in which ionizing radiation exposures have been assessed are illustrated through reference to some studies of childhood leukaemia, concerning environmental, medical, natural and parental occupational exposures. Based on this, implications for the interpretation of radiation epidemiological studies are discussed.

Variants in the ATM Gene Associated with a Reduced Risk of Contralateral Breast Cancer

Between 5% and 10% of women who survive a first primary breast cancer will subsequently develop a second primary cancer in the contralateral breast. The Women's Environment, Cancer, and Radiation Epidemiology Study was designed to identify genetic and environmental determinants of contralateral breast cancer (CBC). In this study, 708 women with asynchronous CBC served as cases and 1,397 women with unilateral breast cancer served as controls. ATM, a serine-threonine kinase, controls the cellular response to DNA double-strand breaks, and has been implicated in breast cancer risk. Complete mutation screening of the ATM gene in all 2,105 study participants identified 240 distinct sequence variants; only 15 were observed in >1% of subjects. Among the rare variants, deleterious alleles resulting in loss of ATM function were associated with a nonsignificant increase in risk of CBC. In contrast, carriers of common variants had a statistically significant reduction in risk of CBC. Four of these 15 variants were individually associated with a significantly decreased risk of second primary breast cancer [c.1899-55T>G, rate ratio (RR), 0.5; 95% confidence interval (CI), 0.3-0.8; c.3161C>G, RR, 0.5; 95% CI, 0.3-0.9; c.5558A>T, RR, 0.2; 95% CI, 0.1-0.6; c.6348-54T>C RR, 0.2; 95% CI, 0.1-0.8]. These data suggest that some alleles of ATM may exert an antineoplastic effect, perhaps by altering the activity of ATM as an initiator of DNA damage responses or a regulator of p53.

Internal irradiation of the thyroid gland in residents of Kaluga Oblast from results of 131I content measurements performed in May 1986

The content of 131 I in the thyroid gland of approximately 30000 residents of Kaluga oblast was measured in May 1986. The work was supported by calibration and verification of the measurement means and procedure. The data making it possible to evaluate the individual, average, median, and collective dose of internal irradiation of the thyroid gland in people of different ages in the populated points of the oblast are presented. The irradiation dose to the thyroid gland in children is much higher than for adults. It is found that the individual dose of internal irradiation to the thyroid gland is described by a nearly log-normal distribution. Some of the individuals examined have an individual dose which is several-fold higher than the average and median dose. This indicates the presence of groups with an elevated radiation risk; attention should be focused on this group first when medical-prophylactic and protective measures are taken. The data from Kaluga oblast, combined with similar results from Bryansk oblast and Belarus, have served as basis for reconstructing the individual absorbed irradiation dose to the thyroid gland and as dosimetric support of radiation-epidemiological studies using the case-monitoring procedure.

Dose to the Contralateral Breast From Radiotherapy and Risk of Second Primary Breast Cancer in the WECARE Study

To quantify the risk of second primary breast cancer in the contralateral breast (CB) after radiotherapy (RT) for first breast cancer. The study population included participants in the Women's Environmental, Cancer, and Radiation Epidemiology study: 708 cases (women with asynchronous bilateral breast cancer) and 1399 controls (women with unilateral breast cancer) counter-matched on radiation treatment. Participants were <55 years of age at first breast cancer. Absorbed doses to quadrants of the CB were estimated. Rate ratios (RR) and 95% confidence intervals (CI) were calculated using multivariable-adjusted conditional logistic regression models. Across all patients, the mean radiation dose to the specific quadrant of the CB tumor was 1.1 Gy. Women <40 years of age who received >1.0 Gy of absorbed dose to the specific quadrant of the CB had a 2.5-fold greater risk for CB cancer than unexposed women (RR = 2.5, 95% CI 1.4-4.5). No excess risk was observed in women >40 years of age. Women <40 years of age with follow-up periods >5 years had a RR of 3.0 (95% CI 1.1-8.1), and the dose response was significant (excess RR per Gy of 1.0, 95% CI 0.1-3.0). Women <40 years of age who received a radiation dose >1.0 Gy to the CB had an elevated, long-term risk of developing a second primary CB cancer. The risk is inversely related to age at exposure and is dose dependent.

Risk for contralateral breast cancer among carriers of the CHEK2*1100delC mutation in the WECARE Study

The protein encoded by the CHEK2 gene is involved in cellular repair of DNA damage. The truncating mutation, CHEK2*1100delC, seems to increase the risk for breast cancer. We investigated whether the CHEK2*1100delC mutation carrier status increases the risk for asynchronous contralateral breast cancer (CBC) and whether it interacts with radiation therapy (RT) or chemotherapy in regard to CBC risk. The germline mutation frequency was assessed in 708 women with CBC and 1395 women with unilateral breast cancer (UBC) in the Women's Environment, Cancer and Radiation Epidemiology (WECARE) Study whose first primary breast cancer was diagnosed before age 55 years and during 1985–1999. Seven women with CBC (1.0%) and 10 women with UBC (0.7%) were CHEK2*1100delC variant carriers (rate ratio (RR)=1.8, 95% confidence interval (CI)=0.6–5.4 for CBC vs UBC). Carriers who received RT for their first breast cancer, compared with non-carriers not treated with RT, had an RR of developing CBC of 2.6 (95% CI=0.8–8.7). We found no significant associations between the CHEK2*1100delC mutation and CBC overall or among those treated with RT. However, the sampling variability was such that modest increases in risk could not be excluded. Nonetheless, because this is a rare mutation, it is unlikely to explain a major fraction of CBC in the population.

Effect of Systemic Adjuvant Treatment on Risk for Contralateral Breast Cancer in the Women's Environment, Cancer and Radiation Epidemiology Study

Results from randomized trials indicate that treatment with tamoxifen or chemotherapy for primary breast cancer reduces the risk for contralateral breast cancer. However, less is known about how long the risk is reduced and the impact of factors such as age and menopausal status. The study included 634 women with contralateral breast cancer (case patients) and 1158 women with unilateral breast cancer (control subjects) from the Women's Environment, Cancer and Radiation Epidemiology Study. The women were younger than age 55 when they were first diagnosed with breast cancer during 1985-1999. Rate ratios (RRs) and 95% confidence intervals (CIs) for contralateral breast cancer after treatment with chemotherapy or tamoxifen were assessed by multivariable adjusted conditional logistic regression analyses. Chemotherapy was associated with a lower risk for contralateral breast cancer (RR = 0.57, 95% CI = 0.42 to 0.75) than no chemotherapy. A statistically significant association between chemotherapy and reduced risk for contralateral breast cancer persisted up to 10 years after the first breast cancer diagnosis and was stronger among women who became postmenopausal within 1 year of the first breast cancer diagnosis (RR = 0.28, 95% CI = 0.11 to 0.76). Tamoxifen use was also associated with reduced risk for contralateral breast cancer (RR = 0.66, 95% CI = 0.50 to 0.88) compared with no use, and the association was statistically significant for 5 years after the first diagnosis. The associations between chemotherapy and tamoxifen treatment and reduced risk for contralateral breast cancer appear to continue for 10 and 5 years, respectively, after the initial breast cancer is diagnosed. Ovarian suppression may have a role in the association between chemotherapy and reduced risk for contralateral breast cancer.