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1 Unité de recherche en santé des populations and 2 Centre des maladies du sein Deschênes-Fabia, Centre hospitalier affilié universitaire de Québec; 3 Department of Social and Preventive Medicine and 4 Laboratoire d'anatomo-pathologie, département de biologie médicale, Laval University; and 5 Clinique Radiologique Audet, Quebec, Quebec, Canada; 6 Departments of Medicine and Oncology, Cancer Prevention Research Unit, Lady Davis Institute of the Jewish General Hospital and McGill University, Montreal, Quebec, Canada; 7 Lombardi Cancer Center, Georgetown University, Washington, District of Columbia; 8 Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; 9 Institut national de santé publique du Québec et Centre de recherche, Hôpital Charles LeMoyne, Greenfield, Quebec, Canada; and 10 Sunnybrook & Women's College Health Sciences Centre, University of Toronto, Toronto, Canada
Requests for reprints: Jacques Brisson, Unité de recherche en santé des populations, Centre hospitalier affilié universitaire de Québec, Hôpital Saint-Sacrement, 1050 Chemin Sainte-Foy, Quebec, Quebec, Canada G1S 4L8. Phone: 418-682-7392; Fax: 418-682-7949. E-mail: jacques.brisson{at}uresp.ulaval.ca
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Abstract |
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Introduction |
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There is growing evidence that IGF-I may contribute to the progression of several human cancers (5, 6), including breast cancer (7), whereas IGFBP-3 has been proposed as an anticancer protein (8). Women with acromegaly have clinically higher levels of IGF-I (9) and have an increased incidence of breast cancer compared with the general population (10-12). Moreover, high circulating levels of IGF-I were consistently found to be positively associated with breast cancer risk in premenopausal women (13-21), with few exceptions (22-25). Among postmenopausal women, some studies observed an IGF-I to breast cancer association (18, 24, 26) but most did not (14-17, 19-21, 23, 25, 27-29). Relationship between levels of IGFBP-3 and breast cancer risk is less clear. In studies conducted in premenopausal women, some observed that higher circulating levels of IGFBP-3 were associated with low breast cancer risk (13, 14), whereas positive (16, 17, 19-21) or null associations (15, 22-24) were found by others. Only two (20, 21) of several studies (14-17, 19, 23, 24, 28, 29) showed a positive association of IGFBP-3 with breast cancer risk in postmenopausal women. Finally, Bohlke et al. (13) examined the joint effect of IGF-I and IGFBP-3 on incidence of ductal carcinoma in situ. Their data suggest that premenopausal women with a combination of high levels of IGF-I and low levels of IGFBP-3 had an elevated risk of ductal carcinoma in situ of the breast compared with those with a combination of low levels of IGF-I and high levels of IGFBP-3.
Mammographic breast density is one of the strongest risk factors for breast cancer (30). Data from three small cross-sectional studies suggest that the extent of mammographic breast density, among premenopausal women, may be associated with high levels of IGF-I and low levels of IGFBP-3 (31-33). No association has been observed among postmenopausal women (31, 32, 34). Thus, the growth factor-breast density associations seem to mirror the growth factor-breast cancer relations.
This cross-sectional study was designed specifically to determine whether plasma levels of IGF-I, IGFBP-3, and the molar ratio IGF-I/IGFBP-3 (an indicator of bioavailability of IGF-I) were separately related to mammographic breast density among premenopausal and postmenopausal women. Data also allowed examination of the combined relation of IGF-I and IGFBP-3 with breast density.
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Materials and Methods |
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To be eligible for the present study, women were either premenopausal if they had at least one natural menstrual cycle within 12 months or were younger than 48 years (if a nonsmoker) or 46 years (if a smoker) after hysterectomy without bilateral oophorectomy or use of hormonal derivatives (35). They were considered postmenopausal if they reported complete cessation of menses for at least 12 months, radiation-induced menopause, or bilateral oophorectomy or were at least ages 56 years (if a nonsmoker) or 54 years (if a smoker) after hysterectomy without bilateral oophorectomy or use of hormonal derivatives (35). Finally, eligibility was restricted to women not taking hormone medication, including oral contraceptives or postmenopausal hormones, within 3 months of the mammography, never having used tamoxifen or raloxifene, not pregnant, without a history of cancer at any site, without breast reduction or implants, and without diabetes mellitus, dwarfism/acromegaly, or thyroid, adrenal, or hepatic disease. No restriction criteria on age were applied.
Eligible women who accepted to participate provided written consent, including authorization for blood sampling and banking of samples, to provide information on breast cancer risk factors, to borrow, digitize, evaluate, and keep a digitized copy of their mammogram, and to review medical records to obtain the results of the mammographic examination, including pathologic findings. Women with known cognitive deficit of any cause were excluded because of impaired ability to provide informed consent.
Of the 9,559 women who received a screening mammogram and were approached, 1,021 refused to participate in our study. In the remaining 8,538 women, 6,924 were ineligible because they were using hormonal derivatives (n = 4,987) or did not meet other eligibility criteria (n = 1,937). A total of 800 premenopausal and 814 postmenopausal women were identified as potentially eligible for the study and provided informed consent. Among these women, 7 women (n = 1 premenopausal and n = 6 postmenopausal) were found ineligible during the interview because they had had a breast reduction (n = 1 postmenopausal), they used hormone replacement therapy within the last 3 months (n = 1 premenopausal and n = 3 postmenopausal), they used raloxifene (n = 1 postmenopausal), or they had uncertain menopausal status (n = 1 postmenopausal). After the review of the reports provided by the radiologists, 9 women (n = 8 premenopausal and n = 1 postmenopausal) were excluded because they did not meet our definition of screening mammogram and 7 women (n = 4 premenopausal and n = 3 postmenopausal) were excluded because the investigation recommended by the radiologists following their screening mammogram led to a diagnosis of breast cancer. In the remaining 787 premenopausal and 804 postmenopausal women, a blood sample could not be obtained for 3 postmenopausal women and film mammograms were not available for 3 women (n = 2 premenopausal and n = 1 postmenopausal). Finally, 10 women (n = 2 premenopausal and n = 8 postmenopausal) declined to be interviewed and 1 postmenopausal woman revoked her participation. Therefore, a total of 783 premenopausal and 791 postmenopausal women were eligible for the present analysis. Of those, 99.5% were recruited at the Clinique Radiologique Audet (n = 1,566) and 8 were recruited at the Clinique de radiologie Saint-Pascal.
Data Collection
Anthropometric Measures and Blood Sampling at Time of Mammography. Women wearing light clothing without shoes were weighed (kg), and height (cm) was measured by a trained research nurse. Waist circumference was measured using a soft tape midway between the lowest rib margin and the iliac crest in the standing position, and hip circumference was measured over the widest of the gluteal region. From these measurements, the body mass index (BMI; kg/m2) and waist-to-hip ratio (WHR; an indicator of central body fat distribution) were obtained. For each woman, blood (20 mL) was drawn and fasting status was recorded as the number of hours since last meal. Anthropometric measures and blood sampling occurred at time of mammography for 95.4% of the subjects (n = 1,501), with an average ± SD of 0.4 ± 1.9 day between the time of the mammogram and when the blood was drawn. For premenopausal women, the first day of the last menstrual cycle was documented. In addition, a calendar was distributed to indicate the first day of the menstrual cycle after their mammogram and to transmit this information during the phone interview. Age (years) at time of the mammogram was recorded for all women. Finally, each woman received a validated (36) and self-administered semiquantitative food frequency questionnaire (97GP copyrighted at Harvard University) and was requested to return it by mail once completed. Intake of foods obtained through the questionnaire was translated into nutrient intake, including energy intake (kcal/d), at the Channing Laboratory of Harvard University (Boston, MA). This semiquantitative questionnaire was answered by 99.3% of women (n = 1,563).
Information during Telephone Interview. Data on potential breast cancer risk factors were collected by trained interviewers using a questionnaire designed for this study. Risk factors for breast cancer included reproductive history, family history of breast cancer, history of breast biopsies, past use of hormonal derivatives, smoking status, alcohol intake, education, and physical activity. For the latter, the level of physical activity in metabolic equivalents-hour/wk was assessed using the Nurses' Health Study II Activity and Inactivity Questionnaire (37) and the classification by Ainsworth et al. (38) for the metabolic equivalent. Phone interviews took place on average ± SD of 27 ± 13 days after the mammogram; 72.7% of the subjects had their interview within 1 month of their screening mammogram.
Digitization of Mammograms and Assessment of Mammographic Features. All mammograms were digitized using a Kodak Lumiscan85 digitizer at 260 µm per pixel (0.067 mm2 per pixel), which creates a 12-bit gray scale image that is linear in the absorbance range 0 to 4.0. Calibration of the scanner was verified before each utilization. All mammograms were reviewed by one of the authors (C.D.). This reviewer was trained in the assessment of breast density using a set of mammographic images (n = 110) previously read by one of the authors (C.B.) who has experience in the assessment of breast density by computer-assisted method (31, 39-41). After the training period, proficiency in assessment of breast density was evaluated comparing C.D.'s readings with those of C.B.'s based on an additional 220 mammograms. The intraclass correlation coefficients of the mammographic features, including breast density and total and dense regions, between these two readers were 0.97, 0.98, and 0.96, respectively.
Assessment of mammographic features was done, without any knowledge of the participants status or medical history, using a computer-assisted method developed by one of us (M.Y.) and described elsewhere (42-44). Breast density was measured for one craniocaudal view for each woman, the right or left view being chosen randomly. The mammograms were read in batches of at least 100 images. A typical batch included one craniocaudal view of 80 women (n = 40 premenopausal and n = 40 postmenopausal). The batch also included 10 images chosen at random among the initial group of 80 images allowing assessment of intrabatch variability. Moreover, in all batches, the same group of 10 images was inserted to assess the interbatch variability. The 100 images of each batch were randomly ordered. For two batches, craniocaudal views of both breasts were included to assess variability of density between left and right breasts. For the mammographic breast density measurements in the present study, the within-batch intraclass correlation coefficient was 0.98 and the between-batch coefficient of variation was 4%. These measures of variability were similar for premenopausal and postmenopausal women. In addition, the mean difference in breast density between the right and the left breasts was 0.56% and the intraclass correlation coefficient between both sides was 0.95. All 21 batches were read within 1 month.
Laboratory Measures of IGF-I and IGFBP-3. At the time of mammography, blood specimens collected were kept on ice until they were submitted for centrifugation. Blood constituents were then aliquoted and stored at –80°C until analysis. Time between blood donation and blood constituents storage, including plasma, was <3 hours for 99.4% of the subjects for an average ± SD of 123 ± 37 minutes. Aliquots of frozen plasma were sent on dry ice in batches of 39 samples for laboratory analyses without any information on women. Blinded split samples were randomly included in each batch (four samples per batch) to allow assessment of intraassay and interassay variabilities of laboratory measurements. Under the supervision of one of us (M.P.), IGF-I and IGFBP-3 were assayed by ELISA with reagents from Diagnostic Systems Laboratory (Webster, TX). For the present study, the intrabatch coefficients of variation were 10.5% and 13.2% and the between-batch coefficients of variation were 7.9% and 10.5% for IGF-I and IGFBP-3, respectively.
Statistical Methods
Univariate and multivariate associations between continuous levels of growth factors (IGF-I, IGFBP-3, or IGF-I/IGFBP-3 molar ratio) and continuous measures of breast density were evaluated with the Spearman correlation coefficient (rs). The molar ratio IGF-I/IGFBP-3 was calculated as: [0.130 x level of IGF-I (ng/mL)] / [0.036 x level of IGFBP-3 (ng/mL)], which has been suggested to reflect availability of IGF-I in tissue (45). Multivariate-adjusted mean breast density by category of growth factors was calculated using generalized linear model sum of squares error estimates. The same approach was used to obtain multivariate-adjusted mean level of growth factors by category of breast density. Statistical significance was based on two-sided Ps.
In the present analysis, factors included as confounders in multivariate models were age (years), BMI (kg/m2), and IGF-I (ng/mL) or IGFBP-3 (ng/mL) among premenopausal women. Among postmenopausal women, parity (yes/no) was also included in models. Further adjustment for factors potentially associated with breast density and/or levels of growth factors (age at menarche, number of full-term pregnancies, age at first full-term pregnancy, lactation, WHR, family history of breast cancer, history of breast biopsies, smoking, alcohol intake, education, past use of oral contraceptive, past use of hormone-replacement therapy, physical activity, and energy intake) did not materially alter the results. Therefore, they were not added in the models. All statistical analyses were carried out using the SAS (SAS Institute, Inc., Cary, NC) software system.
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Results |
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5,000 ng/mL) was higher in premenopausal than in postmenopausal women (64.0% versus 56.9%; Fig. 1A and B). The joint distribution of IGF-I and IGFBP-3 also varied by menopausal status (Fig. 1A and B). For instance, the correlation of IGF-I levels with IGFBP-3 levels was weaker in premenopausal women (rs = 0.552; P < 0.0001) than in postmenopausal women (rs = 0.628; P < 0.0001). The percentage of premenopausal women with a combination of higher levels of IGF-I (>200 ng/mL) and lower levels of IGFBP-3 (5,000 ng/mL) was more than twice the percentage seen among postmenopausal women (31.7% versus 12.7%; Fig. 1A and B). In contrast, the percentage of women with lower IGF-I (200 ng/mL) and higher IGFBP-3 (>5,000 ng/mL) was substantially lower in premenopausal compared with postmenopausal women (4.9% versus 15.9%; Fig. 1A and B).
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25 kg/m2 (rs = 0.013; P = 0.813, rs = –0.090; P = 0.095, and rs = 0.0003; P = 0.996, respectively, for n = 346). Among premenopausal women, 37.1% reported a family history of breast cancer and 91.8% had ever used hormonal derivatives. Correlation of IGF-I, IGFBP-3, and molar ratio with breast density were similar among women without a family history of breast cancer (rs = 0.093; P = 0.041, rs = –0.133; P = 0.003, and rs = 0.084; P = 0.065, respectively, for n = 488) and among those with such a history (rs = 0.065; P = 0.271, rs = –0.121; P = 0.041, and rs = 0.059; P = 0.321, respectively, for n = 288). In contrast, we observed that breast density was more strongly correlated with IGF-I, IGFBP-3, and molar ratio among women that had never used hormonal derivatives (rs = 0.230; P = 0.075, rs = –0.286; P = 0.026, and rs = 0.232; P = 0.070, respectively, for n = 64) compared with women who had ever used hormonal derivatives (rs = 0.066; P = 0.076, rs = –0.105; P = 0.005, and rs = 0.051; P = 0.175, respectively, for n = 719).
Among premenopausal women, correlation of growth factors with breast density were similar among women with regular menstrual cycle (21-35 days) to those with an irregular menstrual cycle or who had an hysterectomy (data not shown). Among women with regular cycles, the magnitude of the correlation between growth factors and breast density was not materially altered by further adjustment of the phase of menstrual cycle at the time of the mammogram (data not shown).
No association of growth factors with breast density was observed within strata of any breast cancer risk factor among postmenopausal women (data not shown).
Eligibility to the present study was restricted to women not taking hormonal derivatives within 3 months of the mammography. Results were essentially unchanged after exclusion of those who used hormonal derivatives within the past 6 or 12 months of the mammography. For instance, exclusion of women using hormonal derivatives within the past 12 months of the mammography had little or no effect on the correlation of IGF-I, IGFBP-3, and molar ratio with breast density in either premenopausal women (rs = 0.088; P = 0.017, rs = –0.125; P = 0.0006, and rs = 0.071; P = 0.052, respectively, for n = 754) or postmenopausal women (rs = 0.031; P = 0.409, rs = –0.019; P = 0.605, and rs = 0.030; P = 0.432, respectively, for n = 713).
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Discussion |
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Among postmenopausal women, all studies to date, including our own, have shown little or no association of IGF-I or IGFBP-3 with breast density (31, 32, 34). Among premenopausal women, results have been less consistent (31-34). One study failed to show an IGF-I to breast density association (34). Among the three studies (31-33) finding that higher IGF-I levels were associated with high breast density, the strength of observed associations varied. Compared with our data, the strength of the correlation was greater in the Nurses' Health Study (ref. 31; rs = 0.36; P = 0.007) but was similar in the study conducted by Maskarinec et al. (ref. 33; rs = 0.11; P = 0.06). Boyd et al. (32) used the coefficient of determination of the unadjusted association (R2 = 0.05) to evaluate this relation impairing such comparison. Two of the studies (31, 33) found that high levels of IGFBP-3 were related to lower breast density. Compared with our findings, the magnitude of the correlation was stronger in the Nurses' Health Study (rs = –0.24; P = 0.07) but not in the study of Maskarinec et al. (rs = –0.15; P = 0.02). Finally, the only histologic study we know of observed that amounts of IGF-I in breast tissue were higher in women with high mammographic breast density compared with amounts in those with low breast density, and this association was stronger for women ages <50 years (46). The presence of associations between growth factors and breast density in premenopausal but not in postmenopausal women might be due, at least in part, to differences in the distribution of IGF-I and IGFBP-3 among these two groups of women. All of the above studies, including ours, observed higher mean/median levels of IGF-I and lower mean/median levels of IGFBP-3 in premenopausal women compared with postmenopausal women (31, 32, 34). In the Nurses' Health Study, correlation of IGF-I and IGFBP-3 levels was also stronger among postmenopausal (rs = 0.59) than in premenopausal (rs = 0.43) women.
Among premenopausal women, we found that the association of IGF-I with mammographic breast density was stronger at low compared with high levels of IGFBP-3. Similarly, the association of IGFBP-3 with breast density was stronger at high compared with low IGF-I levels. Thus, the highest breast density was observed for women with the combination of high IGF-I and low IGFBP-3. To our knowledge, combined IGF-I and IGFBP-3 levels have not been investigated in relation with breast density. However, the combination of high IGF-I with low IGFBP-3 levels is related to an increased risk of ductal carcinoma in situ of the breast among premenopausal women compared with those with a combination of low IGF-I and high IGFBP-3 (13). Prospective data from the Physicians' Health Study on advanced-stage prostate cancer risk (47) and colorectal cancer risk (48) also suggest that patients with a combination of high IGF-I and low IGFBP-3 levels incur the greatest risk.
The strength of association of growth factors with breast density may vary substantially according to some characteristics of women. Among premenopausal women, stronger association of IGF-I and IGFBP-3 levels with breast density was observed among taller women. In addition, a stronger association was observed between IGF-I and breast density in leaner women. These results are consistent with the only previous study that reported a potential modifying effect of BMI, using the WHO cutoff, on the association of IGF-I levels and the molar ratio with breast density, but statistical significance was reached only for the molar ratio (33). Therefore, the variability in the strength of association of growth factors with breast density among premenopausal women observed across studies might be explained, at least in part, by variations in the characteristics of women in those studies. On the other hand, studies that examined the modifying effect of BMI on the association of growth factors with breast cancer risk found inconsistent results (17, 20). For instance, Yu et al. observed a stronger positive association of IGF-I and IGFBP-3 levels with breast cancer risk in a population of premenopausal and postmenopausal women with high BMI or high WHR (20). Muti et al. observed no effect modification of BMI on these associations in premenopausal women but found a stronger positive association between IGF-I levels and breast cancer risk among postmenopausal women with high BMI (17).
This study has several strengths. Firstly, the quality of the mammographic images was maximized. Almost all mammograms were done in the same clinic with the same equipment (mammography units, LORAD M4) that was accredited by the Canadian Association of Radiology in addition to satisfying the high-quality standards of the Quebec breast cancer screening program. This clinic rigorously follows the quality control protocol recommended by the Canadian Association of Radiology, including the development of high-contrast mammographic films. Secondly, quantitative measures of breast density were obtained without any information on women, using a computer-assisted method, in a short period of time, by one reader whose reliability of reading was shown to be high. Although the density of only one breast was measured, the concordance of the measures between right and left breasts in this study was high. Thus, the misclassification of breast density should be relatively small, most likely be random, and therefore should not have biased our results. Thirdly, circulating levels of IGF-I and IGFBP-3 were each measured within 1 month using the same type of reagents for all assays. The laboratory analyses were done without any information on women, and the reliability of these measures was also shown to be high. Thus, our findings are unlikely to be explained by random misclassification of the measurements of the analytes. Fourth, for 95.4% of women, the blood was drawn on the same day as the mammogram, eliminating the potential problem of timing of density and growth factor measurements. Fifth, several factors potentially related to breast density and/or growth factors were documented and their confounding effects were assessed and taken into account when necessary. Finally, the effective sample size is relatively large.
This study has some limitations. Women in the present study reported a family history of breast cancer more frequently than those in other studies on the same topic (31-34). However, associations of growth factors with breast density appeared as strong in women with a family history than in those without such a history. Residual effect by past exogenous hormones use could be possible because eligibility in our study was restricted to women not taking hormonal derivatives within 3 months of the mammography. However, our results were essentially unchanged after exclusion of those who used hormonal derivatives within the past 6 or 12 months of the mammography. Blood collection (and mammography) was not timed with a specific phase of the menstrual cycle among premenopausal women. In our data, phase of the menstrual cycle was associated with levels of IGF-I but not with levels of IGFBP-3 or with breast density. Moreover, additional adjustment for phase of the menstrual cycle at time of the mammogram had essentially no confounding effect in these data. Finally, blood was not drawn after a period of fasting. However, no association was observed between the number of hours since last meal with neither IGF-I, IGFBP-3, nor breast density. Moreover, further adjustment for time since last meal did not materially alter our results.
Mammographic breast density is an estimate of the extent of fibroglandular tissue (including stromal and epithelial cells) in relation to fat. Laboratory studies proposed that IGF-I is able to stimulate both stromal and epithelial human breast cell growth (49, 50). Likewise, IGFBP-3 may have an IGF-independent inhibitory effect on epithelial human breast cell growth (49) but an IGF-dependent inhibitory effect on stromal human breast cell growth (50). Because mammographic breast density is strongly associated with breast cancer risk (30), our results provide additional support for the idea that IGF-I and IGFBP-3 may act on breast cancer development through their influence on the morphogenesis of breast tissue at least among premenopausal women.
The temporality of the relation between growth factors and breast density cannot be determined due to the cross-sectional design. If causality is nonetheless confirmed by prospective data, it will suggest that mammographic breast density should be evaluated as an intermediate marker in studies aimed at developing or evaluating interventions that are thought to act, at least in part, by affecting the IGF-breast cancer pathway.
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Acknowledgments |
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Footnotes |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 9/23/04; revised 1/11/05; accepted 2/21/05.
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) women and the percentage of premenopausal (A) and postmenopausal (B) women by joint levels of IGF-I and IGFBP-3.