Affiliations of authors: F. E. van Leeuwen, W. J. Klokman, E. C. Dahler (Department of Epidemiology), B. M. P. Aleman, N. S. Russell (Department of Radiotherapy), A. Broeks (Department of Experimental Therapy), Netherlands Cancer Institute, Amsterdam, The Netherlands; M. Stovall, Department of Radiation Physics, The University of Texas M. D. Anderson Cancer Center, Houston, TX; M. B. vant Veer, Department of Hematology, Erasmus Medical Center/Daniel den Hoed Cancer Center, Rotterdam, The Netherlands; E. M. Noordijk, Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands; M. A. Crommelin, Catharina Hospital, Eindhoven, The Netherlands; M. Gospodarowicz, the Princess Margaret Hospital, University of Toronto, Ontario, Canada; L. B. Travis, Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD.
Correspondence to: Flora E. van Leeuwen, Ph.D., Department of Epidemiology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands (e-mail: f.v.leeuwen{at}nki.nl).
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ABSTRACT |
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INTRODUCTION |
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The elevated risk of breast cancer following irradiation for HD is not surprising in view of the reported excess risks of breast cancer after other radiation exposures (e.g., from multiple chest fluoroscopies, radiation treatment for benign disease, and the atomic bombings in Japan) (1621). In the low-dose range (5 Gy), breast cancer risk increases linearly with radiation dose (16,17,19,2224). When addressing the possibility of dose reductions in mantle RT for HD, an important unanswered question is whether the linear dose response extends to the higher dose ranges (i.e., 2444 Gy) that are used therapeutically. Although one study found that a higher radiation dose to the mantle region (
20 Gy versus <20 Gy) was associated with a higher risk of breast cancer (2), and some studies reported that most breast tumors arise in or at the margin of the radiation field (2,5,9,25,26), no studies have, to our knowledge, examined the association between individually estimated radiation doses at the precise site of subsequent breast tumor development and breast cancer risk.
Most HD patients are currently treated with a combination of CT and RT. It is not known, however, whether CT-induced premature menopause, associated use of hormone replacement therapy (HRT), or reproductive risk factors affect radiation-associated breast cancer risk in women treated for HD. To investigate these issues, we undertook a casecontrol study in The Netherlands in which we collected detailed information on all relevant risk factors.
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SUBJECTS AND METHODS |
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A nested casecontrol study was conducted in a joint cohort of 2637 patients with HD who were admitted to The Netherlands Cancer Institute in Amsterdam (n = 921), the Dr. Daniel den Hoed Cancer Center in Rotterdam (n = 1016), the Leiden University Medical Center (n = 530), or the Catharina Hospital Eindhoven (n = 170) between 1965 and 1988. Methods used to identify the cohorts in the four centers and to assess second cancer risk have been described extensively elsewhere (11,2729). Twenty-nine percent of the members of the combined cohort (n = 770) consisted of female patients diagnosed with HD at age 40 or younger, and 650 of those patients survived 5 or more years. Follow-up as to the recent medical status of the patients was estimated to be complete for 91% of the cohort members (11).
Case patients were defined as female cohort members who developed histologically confirmed breast cancer at least 5 years after having been diagnosed with HD at 40 years of age or younger. Patients who developed breast cancer within 5 years of HD diagnosis or after an HD diagnosis at 41 years of age or older were not eligible for the casecontrol study because no statistically significant excess risk of breast cancer has been reported for such patients (11,15). For the purpose of this study, ductal carcinoma in situ of the breast, which was diagnosed in one woman, was considered as breast cancer. Patients who had received RT or CT before the diagnosis of HD were excluded. Forty-eight breast cancer patients in the cohort were eligible for study. For all of these patients, the breast cancer diagnosis was confirmed by review of pathology reports.
For each case patient, at least four matched control subjects were sought from the cohort of HD patients. Control subjects were matched to each case patient on age at diagnosis of HD (within 3 years) and date of diagnosis of HD (within 5 years). They also had to have survived without a second cancer for at least as long as the interval between the diagnoses of HD and breast cancer in the case patient. Four or more control subjects were identified for each of 27 case patients, three control subjects were identified for each of 14 case patients, two control subjects were identified for each of four case patients, and one control subject was identified for each of three case patients.
In three centers, case patients and control subjects who were alive in 1998 (n = 154) also were asked to participate in a related study that examined whether ATM heterozygosity increases the risk of radiation-associated breast cancer (30). These patients were also asked to complete a questionnaire on reproductive history and other breast cancer risk factors. The questionnaire was returned by 129 patients (31 case patients and 98 control subjects, response rate = 84%).
Data Collection
For all subjects, full medical records were obtained for detailed data abstraction of all treatments received. When part of the treatment had been given outside the four participating centers, the data abstractors went to the other treating hospitals to collect the relevant data. Information was collected on characteristics of HD (morphology and stage), all CT and RT given for HD, splenectomy, weight, height, reproductive factors (number of full-term pregnancies before and after HD diagnosis, cessation of menstruation after CT, and age at menopause), use of HRT, and family history of cancer. For each course or cycle of CT, the details abstracted included the name and total dose of each drug used, the dates of administration, and whether it was given in combination with other cytostatic drugs. For RT, we abstracted from the radiation chart the dose and location of the fields irradiated. In addition, all radiation treatment charts were photocopied for later use in estimating dose to the area of breast tumor development. For breast cancer case patients, we also collected data on laterality, location of breast tumor, stage, morphology and treatment of breast cancer, and occurrence of contralateral breast cancer.
The questionnaire given to the patients in the ATM study asked about age at menarche, age at first and subsequent births, duration of each pregnancy, number of miscarriages, changes in menstrual cycle characteristics after CT and pelvic RT, age at menopause, use of exogenous hormones (brand name and duration of all oral contraceptives and hormone replacement drugs ever used), and family history of cancer.
Complete data on menopausal status, age at menopause, and parity before and after HD were eventually available for 99% of the patients included in our casecontrol study. Complete data on age at menarche and age at each subsequent pregnancy were available for 79% of the study population.
Radiation Treatments and Dosimetry
Of the 220 patients who received RT (all of the case patients and 172 of the 175 control subjects), all but two had treatment with mantle, supraclavicular, mediastinal, axillary, or splenic fields, the fields that give the highest dose to the breast. Most of the patients (78%) were treated with high-energy photons, usually 8 MeV; the remainder were treated with orthovoltage x-rays, cobalt-60, or electrons. The average tumor doses for mantle RT were 38.5 Gy (median = 40 Gy) for case patients and 37.6 Gy (median = 39.8 Gy) for control subjects.
The aim of the dosimetry study was to estimate the actual absorbed dose to the site of the breast cancer and the ovaries. For each subject in a casecontrol set, the radiation dose was estimated as the dose to the site of breast tumor development in the case patient and the dose to a comparable location in the control subjects. Absorbed radiation doses to unblocked fields were based on experimental measurements in a water phantom to 60 cm outside the field (31,32). The dose to blocked fields was estimated as a percentage of the in-beam full dose (using beam data from the machine type used for a particular patient). Correction factors were applied with the use of the Pinnacle-3 treatment Planning system (ADAC Laboratories, Milpitas, CA), based on tumor distance from block edge. Dosimetry was based on details of RT abstracted from the radiation charts, simulation films of all radiation treatments, and copies of the mammograms (or other diagnostic test results) that indicated the precise location of the breast tumor. Each patients record was reviewed by a radiation oncologist, a physicist, and a dosimetrist for position of the breast tumor site relative to the treatment fields. Tumor sites were determined to be either in a radiation beam (blocked or unblocked), on the edge of a beam or a block, or outside of a beam. The dose estimates included contributions from all fields. Attenuation by the lung blocks was included in the breast doses from treatments in the chest. Ovaries were assumed to be in normal position unless the record indicated that the patient had had an oophoropexy.
Statistical Analysis
The odds ratio of breast cancer associated with specific exposures (e.g., radiation dose or CT) was estimated by comparing the case patients exposure histories with those of their matched controls, using conditional logistic regression methods (33). Odds ratios were used as valid risk estimates of RRs and are therefore referred to as such. RR estimates, P values, and 95% confidence intervals (CIs) for the RR estimates were calculated with the microcomputer program EGRET (34), and comparisons between exposure categories were based on likelihood ratio tests. All tests of statistical significance were two-sided. Because all subjects had received RT, CT, or both, it was not possible to estimate the RR of specific treatments as compared with a reference category of subjects never exposed to possible carcinogenic agents. Furthermore, only three patients (all control subjects) had received CT alone, making it impossible to directly compare the risks associated with RT alone with those associated with CT alone. Therefore, in our crude treatment analyses, the RR for patients treated with RT and CT was estimated relative to those treated with RT alone.
For each case patient, we considered only the therapies and reproductive events in the period between the diagnoses of HD and breast cancer; for the corresponding control patient(s), the analysis took into account only the therapy abstracted from a period of equal length, starting with the diagnosis of HD. Throughout the manuscript, for all patients, the end of the coding period is denoted as the cutoff date.
In evaluating the association between breast cancer risk and RT, we used, for each casecontrol set, the radiation dose to the area of the breast where the breast cancer of the case patient had developed. For the seven patients who were diagnosed with contralateral breast cancer, the radiation dose to the site of the first breast cancer was used in all analyses. Risk of breast cancer was either estimated with breast radiation dose treated as a continuous variable or grouped according to quartiles. Radiation dose to the ovaries was dichotomized on the basis of mean dose (5 Gy versus <5 Gy). If the ovaries had received different doses, we used the lower dose in the analysis. The number of CT cycles with alkylating agents (i.e., mechlorethamine and procarbazine) was also treated as a continuous variable or was categorized into fewer than six or six or more cycles.
Multivariable analyses were done to account for potential confounding effects of pregnancies before and after HD, total number of children, age at birth of first and last child, menopausal status, age at menopause, family history of breast cancer, HRT, use of oral contraceptives, and body mass index (BMI; weight in kilograms divided by height in meters squared). When examining the association between CT and breast cancer risk, we initially adjusted for radiation dose only and not for menopausal status and age, because these variables can be considered intermediate factors in the causal pathway between CT and breast cancer risk. Subsequently, to examine whether CT has an effect on breast cancer risk independent of its effect on ovarian function, we also adjusted for menopausal status and age.
We examined whether number of years with intact ovarian function after irradiation for HD affected breast cancer risk. (Because we matched on age at diagnosis of HD there was too little variation in number of years with intact ovarian function before HD to examine this variable.) In women who were postmenopausal at the cutoff date, the time period with intact ovarian function after HD was calculated by subtracting the patients age at first irradiation from her age at menopause, taking into account possible episodes (>1 year) without menstrual cycles immediately after treatment for HD. For women who were premenopausal at the cutoff date, we subtracted age at first irradiation from age at cutoff date.
Interactions between radiation dose to the relevant breast area and CT (or menopausal status or number of years with intact ovarian function after HD treatment) were examined in various models, with radiation dose and CT (or menopausal variables) being treated as either continuous or categorical variables.
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RESULTS |
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A greater number of cycles with alkylating CT was associated with a statistically significantly decreased risk of breast cancer. Patients who had six or more cycles of CT had an adjusted RR of 0.33 (95% CI = 0.13 to 0.86) compared with patients who had received RT alone (Table 2). A radiation dose to the ovaries of 5 Gy or more was also associated with a decreased risk of breast cancer (RR = 0.13, 95% CI = 0.02 to 1.08). The modifying effect of CT on the risk associated with RT was evaluated by fitting radiation doseresponse slopes simultaneously for subjects who had and who had not received CT (Table 3
). For patients who received RT alone, the risk of breast cancer increased strongly with increasing radiation dose (Ptrend = .003); patients who received a dose of 38.5 Gy or more had an RR of 12.7 (95% CI = 1.8 to 86). No such trend was observed among patients who were treated with CT plus RT. The difference in doseresponse trends between the two treatment categories was statistically significant (P = .008). For patients treated with RT alone, the ERR/Gy was 0.06 (95% CI = 0.01 to 0.13).
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We next evaluated associations with reproductive risk factors known to affect breast cancer risk in the population at large. Women who had given birth before they were treated for HD had a slightly reduced risk of breast cancer, whereas women with successful pregnancies after HD had a slightly elevated risk (Table 6); neither change, however, was statistically significant. The use of HRT was uncommon in The Netherlands in the era during which most of the patients in our study entered menopause. Only three case patients and 38 control women had used HRT for a median duration of 3 years (Table 6
). HRT use (versus no use) and use for 3 years or more (versus use for <3 years) were not associated with a statistically significant increase in breast cancer risk. We also examined the effect of BMI among women who were postmenopausal at the cutoff date. Postmenopausal women with a BMI above the median of 21.2 kg/m2 did not have a statistically significantly higher risk of breast cancer than women with a lower BMI (RR = 3.95, 95% CI = 0.69 to 22.8; P = .12). Age at first birth, age at menarche, and oral contraceptive use did not appear to be related to the risk of breast cancer, but numbers in subcategories were small.
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DISCUSSION |
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Despite a large number of experimental and epidemiologic studies, the effect of radiation dose on tumor induction is not yet fully understood. The incidence of radiation-induced tumors is well known to rise in the low-dose range (16,17,19,2224), and it has been speculated that the risk declines with increasing radiation dose as radiation cell kill becomes the predominant effect. For leukemia, a downturn of the risk at a bone marrow dose of several Gy has been shown, although the data are not entirely consistent (23). For breast cancer and other solid tumors, there is convincing evidence for a strongly linear radiation dose response in the lower dose ranges (up to 5 Gy) (16,17,19,22,24,36,37), but very few data are available with regard to shape of the doseresponse curve in the (therapeutic) high-dose range (2444 Gy). Mantle field irradiation exposes the medial and lateral portions of the breast to direct radiation, and the remaining blocked areas receive from 3% to 15% of the dose delivered, depending on the size of the breasts and the position of the patient (3841). Hence, typical mantle treatment with a midline dose of 40 Gy results in a large dose gradient across the breast (342 Gy). Our data show increasing risk of breast cancer over this entire dose range, with no evidence of a decline in risk at the highest doses. However, the slope of the radiation doseresponse curve appears to be less steep than observed in epidemiologic studies covering the lower dose ranges (05 Gy) (1618,21,24). Therefore, it is possible that the linear doseresponse function consistently observed for the low dose ranges attenuates at the high doses used in cancer treatment. In this regard, it is of interest that a recent study of lung cancer risk following RT for HD also reported an upward trend in lung cancer risk with increasing radiation dose up to 40 Gy or more (42).
Only a few studies have examined the effect of CT on the risk of breast cancer following radiation for HD. In three studies, CT was associated with reduced breast cancer risk (11,13,43), although Hancock et al. (5) reported that the addition of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP)-containing combination CT to RT increased breast cancer risk. CT can cause premature menopause, which is known to decrease breast cancer risk considerably in the population at large (44). Indeed, shortly after the introduction of combination CT in HD treatment, it became clear that female patients often experience temporary or permanent ovarian failure after intensive CT (4548). However, few studies have examined menopausal age in women whose ovarian function was retained or recovered after CT during adolescence or young adulthood (49). Our data show that a high percentage (44%) of control women treated with RT and any type of CT reached menopause at age 40 or before; more than half of these women experienced permanent ovarian failure shortly after treatment, but, strikingly, approximately 40% did not experience premature menopause until 5 or more years after CT, likely as a result of CT-induced depletion of the follicle pool in the ovaries. The reduced risk of RT-associated breast cancer in HD patients also treated with CT was most likely due to CT-induced premature menopause. We also found that pelvic irradiation resulting in an ovarian dose of 5 Gy or more was associated with reduced breast cancer risk, presumably through its effect on ovarian function.
In our study, women with a very premature menopause (before age 36) had a 94% lower risk of breast cancer than women who did not have a premature menopause, and women exposed to endogenous ovarian hormones for less than 5 years following RT experienced a risk reduction of 85%. Although our estimate for the risk reduction associated with a very premature menopause (before age 36) was imprecise because it was based on only one case patient and 39 control women, the extent of the risk reduction appears to be even greater than is seen in non-irradiated populations (44).
Because the long-term use of HRT for menopausal symptoms has been shown to increase breast cancer risk (50), it seems possible that HRT use might diminish the risk reduction associated with premature menopause. In the hospitals involved in this study, however, HRT for treatment of CT-induced menopause was prescribed only rarely for women with HD treated before the 1980s. Only 10% of the women in our study used HRT for 3 years or more. This was an advantage in that it allowed us to assess the effect of loss of ovarian function without the confounding effects of subsequent hormone supplementation; however, it was a disadvantage in that our estimates for the reduction of breast cancer risk associated with CT-induced premature menopause do not reflect current treatment policy. Long-term HRT is now commonly prescribed for HD patients to address the adverse consequences of early menopause on bone density and quality of life.
Very few studies have evaluated interactions between radiation dose and other risk factors for breast cancer, such as reproductive factors (36,51,52). However, such studies are important for identifying population subgroups that are at increased risk for the development of radiation-induced breast cancer. Furthermore, we may learn from interaction effects why radiation dose is much more effective in causing breast cancer when exposure occurs at an early age (51). Land et al. (51) found that, in Japanese atomic bomb survivors, radiation dose and nulliparity (as well as late age at first birth) act multiplicatively in the causation of breast cancer. This would imply that the absolute excess risk of developing radiation-induced breast cancer is much lower in parous women than nulliparous women, as well as in women who are younger at first birth than women who are older. In tuberculosis patients exposed to several chest fluoroscopies, superadditive departures from additivity (in the direction of a multiplicative effect) were found for radiation dose and nulliparity (36). However, no significant departure from additivity was found for the joint effects of reproductive variables and radiation dose in a postpartum mastitis cohort (52). The age- and dose-specific absolute excess rates of breast cancer have been found to be remarkably similar across studies in the Japanese atomic bomb survivors and in medically irradiated populations in the United States, implying interaction at the additive level between radiation dose and the risk factors underlying the much greater breast cancer risk in American women than Japanese women (37). In our study, which evaluated much higher radiation doses than the above-mentioned reports, we found some evidence for interaction at the multiplicative level between radiation dose and CT (Table 3), or (CT-induced) premature ovarian failure (Table 5
). That is, among patients who had radiation alone, most of whom were still premenopausal at the end of follow-up, the increase in breast cancer risk with radiation dose was greater than it was among patients who had additional CT, more than half of whom became postmenopausal during follow-up and therefore had less than 15 years exposure to endogenous ovarian hormones. This observation implies that risks associated with exposure to endogenous estrogens appeared to at least multiply risks associated with radiation.
When evaluating the results of our study, several strengths and weaknesses should be considered. A unique feature of our study is that we estimated radiation dose to the precise location where the breast cancer had developed. However, although we were able to use simulation films of the original HD radiation treatment and mammograms indicating tumor location for nearly all patients, some inaccuracies in breast dosimetry were inevitable, depending on the size and the position of the breast. Inaccuracies were particularly likely for tumors located near the edge of the radiation fields and for those in large breasts, especially if the size of the breast increased in the years after RT. Another strength of our study is that, through a questionnaire addressed to the women themselves, we obtained nearly complete data on hormonal risk factors. However, a limitation of our study is the relatively small number of breast cancer patients. As a result, the study did not have sufficient power to examine the role of risk factors that are less strongly associated with breast cancer than radiation dose and early menopausal age, such as pregnancies before and after treatment for HD. The effects of radiation dose in more detailed categories will be examined in a larger international casecontrol study of breast cancer following HD coordinated by the National Cancer Institute of the United States (53).
Our results have several clinical implications. First, the strong radiation doseresponse relationship up to at least 40 Gy emphasizes the importance of minimizing radiation doses and fields without compromising the excellent cure rates (54) that have been achieved for HD. Our results suggest that the lower radiation doses and reduced fields applied in current HD trials may already be expected to attenuate the increased breast cancer risk in more recently treated patients. Until there is evidence of substantially reduced risk with newer treatments, however, the follow-up of women treated with mantle field irradiation before age 30 should include at least yearly clinical breast examination and annual mammography beginning 8 years after irradiation (3,55,56). The importance of regular breast examinations over an extended period should be explained to young women with HD, and they should be taught breast self-examination. Because the efficacy of screening methods for this special patient group is unknown, a study examining the efficacy of various imaging modalities (including magnetic resonance imaging) would be worthwhile (3).
Finally, our finding that breast cancer risk following RT is strongly reduced in women who have experienced CT-induced premature menopause has implications for potential chemopreventive strategies. In other high-risk populations, such as BRCA1 and BRCA2 mutation carriers, several breast cancer chemoprevention trials are in progress worldwide. Because the risk of developing breast cancer at a young age is about equally high in women irradiated for HD as adolescents or young adults, chemoprevention studies aiming to reduce exposure to ovarian steroids in this population are an important next step.
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NOTES |
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We thank A. W. van den Belt-Dusebout for assistance in data collection, A. A. M. Hart for statistical advice, G. M. M. Bartelink for critical comments, and Susan A. Smith for assistance with dosimetry calculations.
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Manuscript received October 25, 2002; revised April 17, 2003; accepted April 24, 2003.
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