Premenopausal Breast Cancer: Estrogen Receptor Status and Insulin‐Like Growth Factor‐I (IGF‐I), Insulin‐Like Growth Factor Binding Protein‐3 (IGFBP‐3), and Leptin

To the Editor: The serum endocrine factors such as insulin-like growth factor I (IGF-I), IGF binding protein-3 (IGFBP-3), and leptin have been linked with premenopausal breast cancer (1–3). Several reports have evaluated these endocrine factors in relation to breast cancer estrogen receptor (ER) status. In postmenopausal Danish women, higher levels of IGFBP-3 are associated with ER positive breast cancer while no link was found with IGF-I (4). Conversely, Goodwin et al. report higher levels of IGFBP-3 and leptin in association with ER negative disease in a cohort comprised of both pre and postmenopausal women (5,6). While Chen, in a smaller sample, found no association between leptin levels and tumor ER status. The associations of the IGF pathway and leptin in premenopausal breast cancer only are not known. Menopausal status may be of particular importance in respect to these body size-related factors as the IGF factors and obesity have contrary effects on breast cancer risk in pre versus postmenopausal women. To better determine the relationship of these factors we examined a group of premenopausal women with newly diagnosed breast cancer to further define the relationships between tumor ER status, the IGF pathway, and leptin. We hypothesized that high IGF-I, high leptin, and low IGFBP-3 levels would be associated with ER-positive disease status compared with ER-negative tumors and that BMI may modify this association, such that the associations would be stronger among larger premenopausal women. Cases were enrolled in two trials that shared a protocol for eligibility, blood draws, and a demographic and body composition questionnaire at The University of Texas M. D. Anderson Cancer Center from March 1998 to March 2001. Participants were premenopausal women of age 18–52 years who were diagnosed with non-invasive or early stage invasive breast cancer within 6 months of study enrollment and had received no chemo or hormonal therapy prior to blood draw. One hundred eight premenopausal cases (82 ER-positive, 26 ER-negative) with stored serum, questionnaire data, and breast cancer pathology reports were available for analysis. Serum samples were drawn at the time of study entry and stored frozen at )70 F. Samples were analyzed for total IGF-I, IGFBP-3, and leptin by sandwich-type ELISAs (Diagnostic Systems Laboratories, Inc. Webster, TX). For IGF-I, duplicate aliquots of each serum sample were pretreated according to the manufacturer’s instructions and assayed; IGFBP-3 and leptin were also assayed in duplicate. Individual samples with %CV >15% were reassayed as above to obtain values with %CV <15% and only results for tests with %CV <15% are reported. The mean values of the duplicate results from each individual were used in the data analysis. After evaluating distributions for normality, baseline characteristics were compared by t-test or Chi-square as appropriate. Tertile cut points for IGF-I, IGFBP-3, and leptin were determined by using the data from the ER-positive cases as the referent group. To capture the amount of unbound IGF-I, we analyzed the ratio of IGF-I to IGFBP-3. For analysis of IGF-I, IGF-I ⁄ IGFBP-3 ratio, and leptin, the lowest two tertiles were combined and compared with the highest tertile. For IGFBP-3, the top two tertiles were combined and compared with the lowest tertile. We also compared differences in mean hormone levels in normal weight women to those of their overweight and obese counterparts combined. The significance of differences between mean hormone levels by ER status was tested by using the Students t-test. Univariate and multivariable logistic regression was used to calculate odds ratios as estimates of relative risks predicting risk of ER-negative disease versus ER-positive disease for high Address correspondence and reprint requests to: Jennifer Eng-Wong, MD, MPH, Lombardi Comprehensive Cancer Center, Georgetown University, 3800 Reservoir Rd. NW, Washington DC 20007, USA, or e-mail: je95@georgetown.edu.