Vol. 9, 161–166, February 2000 Cancer Epidemiology, Biomarkers & Prevention 161 Risk and Aggressiveness of Breast Cancer in Relation to Plasma Organochlorine Concentrations1 Alain Demers, Pierre Ayotte, Jacques Brisson, We conclude that exposure to persistent, hormonally Sylvie Dodin, Jean Robert, and E´ ric Dewailly2 active organochlorines during adulthood is not associated Unite´de Recherche en Sante´Publique, Centre de Recherche du Centre with breast cancer risk. The possibility that some Hospitalier de l’Universite´Laval, Centre Hospitalier Universitaire de Que´bec, organochlorines and especially p,p؅-DDE may increase Beauport, Que´bec, G1E 7G9 Canada [A. D., P. A., S. D., E´ . D.]; Groupe de breast cancer aggressiveness deserves further attention. Recherche en E´ pide´miologie et Centre des Maladies du Sein, Pavillon Saint- Sacrement, Centre Hospitalier Affilie´Universitaire de Que´bec, Que´bec, G1S 4L8 Canada [J. B., J. R.]; De´partement de Me´decine Sociale et Introduction Pre´ventive, Faculte´deMe´decine, Universite´Laval, Ste-Foy, G1K 7P4 Canada [P. A., J. B., E´ . D.]; and Unite´de Recherche en Endocrinologie de la Exposure to environmental chemicals and particularly to or- Reproduction, Centre de Recherche du Pavillon Saint-Franc¸ois-d’Assise, ganochlorines has been suggested as a possible cause of breast Que´bec, G1L 3L5 Canada [S. D.] cancer (1). This group of persistent, lipophilic chemicals com- prises industrial compounds such as PCBs3 and agricultural pesticides, such as chlordane, DDT, and mirex, which were Abstract extensively used in the past and can be found in all ecosystems Several organochlorines identified as “hormone mimics” of the planet. Biological half-lives of several years have been were proposed as possible risk factors for breast cancer. documented in humans for the most persistent organochlorines We conducted a case-control study to assess breast cancer (2, 3), resulting in their accumulation with age in body fat, risk and disease aggressiveness in relation to plasma including adipose tissue (4), blood lipids (5), and milk fat (6). concentrations of several organochlorine compounds. Studies conducted 30 years ago revealed the estogenic proper- Plasma lipid concentrations of 11 chlorinated ties of several commercial mixtures of PCBs and of o,pЈ-DDT, pesticides and 14 polychlorinated biphenyl congeners a minor constituent of technical DDT (7, 8). Since that time, were measured in 315 women newly diagnosed with several other organochlorines (p,pЈ-DDT, chlordane, dieldrin, breast cancer, 219 hospital-based controls, and 307 endosulfan, ␤-HCH, toxaphene) were shown to elicit estrogenic population controls from the Quebec City area (Canada). responses in various in vitro systems (9–11). Given the sus- Concentrations of hormonally active organochlorines or pected implication of estrogens in the pathogenesis of breast their surrogates were compared between cases and cancer (12), it has been proposed that these weakly estrogenic controls as well as between groups of cases defined organochlorine compounds might be a risk factor for the dis- according to tumor size and axillary-lymph-node ease. This hypothesis is supported by results of experimental involvement. studies in rats showing that o,pЈ-DDT can alter mammary gland We found similar levels of organochlorines in cases differentiation and cell proliferation (13) and promote the and controls and no relationship between the relative risk growth of mammary tumors (14, 15). of breast cancer and organochlorine exposure. However, Results from early human studies generally supported the the probability of lymph-node invasion among cases existence of a relationship (16–19) or suggested a possible link increased with exposure to 1,1-dichloro-2,2-bis(4- (20) between breast cancer risk and organochlorine exposure, .chlorophenyl)ethylene [p,p؅-DDE; odds ratio, 2.54; 95% more specifically with p,pЈ-DDE, the main metabolite of DDT confidence interval (CI), 1.20–5.35; between the highest In contrast, recent studies involving larger sample sizes yielded and the lowest tertiles]. Furthermore, p,p؅-DDE exposure negative results (21–25). In particular, Hunter et al. (21) and was associated with a dose-related increased relative risk Høyer et al. (25), using a nested case control study design, of exhibiting both lymph-node involvement and a large failed to observe a relationship between p,pЈ-DDE or PCB tumor. Indeed odds ratio raised to 2.33 (95% CI, 0.94– plasma concentrations and breast cancer risk. However, Høyer 5.77) for the second tertile relative to the first tertile and et al. (25) reported that high plasma concentrations of dieldrin reached 3.51 (95% CI, 1.41–8.73) for the third tertile were associated with breast cancer risk. relative to the first tertile. Similar associations were noted Previous studies have focused solely on the risk of devel- with ␤-hexachlorocyclohexane, oxychlordane, and trans- oping a new breast cancer. However, hormonally active or- nonachlor. ganochlorines might also modulate cancer growth. The present study tests the hypothesis that the risk of developing breast cancer is related to exposure to selected organochlorines that Received 6/4/99; revised 11/2/99; accepted 11/30/99. 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 3 The abbreviations used are: PCB, polychlorinated biphenyl; DDT, dichlorodi- accordance with 18 U.S.C. Section 1734 solely to indicate this fact. phenyltrichloroethane; o,pЈ-DDT, 2-(2-chlorophenyl)-2-(4-chlorophenyl)-1,1,1- 1 Supported by Grant 4811-82 from the National Cancer Institute of Canada. trichloroethane; p,pЈ-DDT, 2,2-bis(4-chlorophenyl)-1,1,1-trichloroethane; p,pЈ- 2 To whom requests for reprints should be addressed, at Unite´de Recherche en DDE, 1,1-dichloro-2,2-bis(4-chlorophenyl)ethylene; ␤-HCH, ␤-hexachlorocyclo- Sante´ Publique, 2400 d’Estimauville, Beauport, Que´bec, G1E 7G9 Canada. hexane; BMI, body mass index; OR, odds ratio; CI, confidence interval; ER, estrogen E-mail: [email protected]. receptor. Downloaded from cebp.aacrjournals.org on October 2, 2021. © 2000 American Association for Cancer Research. 162 Organochlorine and Breast Cancer either possess estrogenic properties themselves or are surro- phospholipids, and triglycerides were quantified by enzymatic gates of past exposure to less persistent estrogenic compounds. assays. In addition, we also investigated the possible relationship be- Statistical Analysis. Characteristics of cases were compared tween exposure to organochlorines and two indicators of breast to those of control groups using Student’s t tests for continuous cancer aggressiveness and prognosis: axillary-lymph-node in- variables or ␹2 tests for categorical variables. Variance analysis volvement and tumor size. was used to compare the mean concentrations of organochlo- rines between cases and controls. Organochlorine concentra- tions in plasma lipids displayed log-normal distributions and Materials and Methods therefore, these statistical analyses were performed using the Subjects. From October 1994 to March 1997, 315 women with natural logarithm of organochlorine concentrations. A concen- histologically confirmed infiltrating primary breast cancer and tration equal to half the detection limit was assumed for sam- 219 controls were recruited in four hospitals of the Quebec City ples with organochlorine levels below the detection limit. area (Quebec, Canada). A second control group included 307 Point and interval estimates of relative risk were based on women randomly selected from the general population files of unconditional logistic regression analysis. Quintile and tertile the Re´gie de l’Assurance maladie du Que´bec. Cases and con- limits of plasma organochlorine concentrations were based on trols were matched for age (5-year age groups) and region of the distribution observed among controls. Risks were calculated residence (rural/urban). Cases were excluded if they had a relative to the lowest category. Age (30–40Ͻ, 40–50Ͻ,50– previous history of breast cancer or any other cancer (except 60Ͻ, Ն60 years) and region of residence (rural/urban) were cervical intraepithelial neoplasm or basocellular skin cancer) or included in all multivariate models. The other variables tested 2 if they showed distant metastasis at diagnosis. All participants for confounding were BMI (kg/m ), total energy consumed, had to reside in the Quebec City area and be aged between 30 alcohol consumption, age at first cigarette, number of fertile and 70 years. Hospital controls had, in addition, to be free of years, age at first child, total breast feeding duration, use of oral gynecological illnesses; they were admitted for digestive sur- contraceptive, use of hormone therapy, first-degree family his- gery (50%), orthopedic surgery (25%), vascular surgery (14%), tory of breast cancer, history of benign breast disease, and time or other surgeries (11%). Participation rates were 91% for separating blood sampling from surgery. A variable was con- cases, 89% for hospital controls, and 47% for population con- sidered as a confounder when its inclusion in the model mod- trols. ified OR (adjusted for age and region of residence) by Ͼ10%. Blood samples were obtained from cases and hospital All statistical analyses were performed using the SAS software controls after surgery and for cases before the initiation of (SAS Institute Inc., Cary, NC). Ͻ chemotherapy or radiotherapy. A research nurse