Use of four biomarkers to evaluate the risk of breast cancer subtypes in the women's contraceptive and reproductive experiences study
Hongli Ma, Yuanyuan Wang, Jane Sullivan‐Halley
Giske Ursin, Michael S Simon, Kathleen E Malone, Jill A McDonald, Michael F Press, Leslie Bernstein, Ronald T Burkman , Polly A Marchbanks , Robert Spirtas , Brian L Strom, Jane Sullivan-Halley, Linda Weiss
Division of Cancer Etiology, Department of Population Sciences, City of Hope Medical Center, Duarte, California; Departments of 2Preventive Medicine and 3Pathology, Keck School of Medicine, Univers...ROR
Division of Cancer Etiology, Department of Population Sciences, City of Hope Medical Center, Duarte, California; Departments of 2Preventive Medicine and 3Pathology, Keck School of Medicine, Univers...
Epidemiologic studies suggest that some hormone-related risk factors in breast cancer differentially influence risk for disease subtypes classified by the status of the estrogen and progesterone receptors (ER/PR). However, it remains unclear whether human epidermal growth factor receptor 2 (HER2) or p53 expression status further differentiates these exposure-risk group associations. We evaluated the associations of oral contraceptive (OC) use and reproductive factors with incident invasive breast cancer subtypes among 1,197 population-based cases and 2,015 controls from the Los Angeles County or Detroit components of the Women's Contraceptive and Reproductive Experiences Study. Case-control comparisons by ER/PR/HER2/p53 status were conducted by multivariable polychotomous unconditional logistic regression methods. We found that OC use was not associated with any breast cancer subtype as defined by ER/PR/HER2/p53 status, except for a 2.9-fold increased risk of so-called triple-negative tumors (ER(-)/PR(-)/HER2(-)) among women of 45 to 64 years of age who started OC use before age 18. Parity was associated with a decreased risk of luminal A (ER(+) or PR(+), HER2(-)), luminal B (ER(+) or PR(+)/HER2(+)), and ER(-)/PR(-)/HER2(+) tumors. Age at first full-term pregnancy was positively associated with luminal A tumors among older women. Neither of these reproductive factors was associated with triple-negative tumors. Long duration of breast-feeding lowered the risk of triple-negative and luminal A tumors. p53 status did not define further differential risk patterns. Our findings offer evidence of differences in the hormone-related risk factors between triple-negative cancers and other ER/PR/HER2-defined subtypes of breast cancer.
breast cancer subtypes, oral contraceptive breast cancer risk, estrogen receptor progesterone receptor, HER2 status, p53 expression, CARE study, hormonal risk factors breast cancer, reproductive history cancer risk, biomarker breast cancer classification, case-control breast cancer
PMID 20068186 20068186 DOI 10.1158/0008-5472.CAN-09-3460 10.1158/0008-5472.CAN-09-3460 Ma et al. 2010, Ma 2010
Cite this article
Ma, H., Wang, Y., Sullivan-Halley, J., Weiss, L., Marchbanks, P. A., Spirtas, R., Ursin, G., Burkman, R. T., Simon, M. S., Malone, K. E., Strom, B. L., McDonald, J. A., Press, M. F., & Bernstein, L. (2010). Use of four biomarkers to evaluate the risk of breast cancer subtypes in the women's contraceptive and reproductive experiences study. Cancer Research, 70(2), 575-587. https://doi.org/10.1158/0008-5472.CAN-09-3460
Ma H, Wang Y, Sullivan-Halley J, Weiss L, Marchbanks PA, Spirtas R, et al. Use of four biomarkers to evaluate the risk of breast cancer subtypes in the women's contraceptive and reproductive experiences study. Cancer Res. 2010;70(2):575-587. doi:10.1158/0008-5472.CAN-09-3460
Ma, H., et al. "Use of four biomarkers to evaluate the risk of breast cancer subtypes in the women's contraceptive and reproductive experiences study." Cancer Research, vol. 70, no. 2, 2010, pp. 575-587.
Previous studies of oral contraceptives and breast cancer indicate that recent use slightly increases risk, but most studies relied on self-reported use and did not examine contemporary oral contraceptive formulations. This nested case-control study was among female enrollees in a large U.S. integrated health care delivery system. Cases were 1,102 women ages 20 to 49 years diagnosed with invasive breast cancer from 1990 to 2009. Controls were randomly sampled from enrollment records (n = 21,952) and matched to cases on age, year, enrollment length, and medical chart availability. Detailed oral contraceptive use information was ascertained from electronic pharmacy records and analyzed using conditional logistic regression, ORs, and 95% confidence intervals (CI). Recent oral contraceptive use (within the prior year) was associated with an increased breast cancer risk (OR, 1.5; 95% CI, 1.3-1.9) relative to never or former OC use. The association was stronger for estrogen receptor-positive (ER(+); OR, 1.7; 95% CI, 1.3-2.1) than estrogen receptor-negative (ER(-)) disease (OR, 1.2, 95% CI, 0.8-1.8), although not statistically significantly different (P = 0.15). Recent use of oral contraceptives involving high-dose estrogen (OR, 2.7; 95% CI, 1.1-6.2), ethynodiol diacetate (OR, 2.6; 95% CI, 1.4-4.7), or triphasic dosing with an average of 0.75 mg of norethindrone (OR, 3.1; 95% CI, 1.9-5.1; Pheterogeneity compared with using other oral contraceptives = 0.004) was associated with particularly elevated risks, whereas other types, including low-dose estrogen oral contraceptives, were not (OR, 1.0; 95% CI, 0.6-1.7). Our results suggest that recent use of contemporary oral contraceptives is associated with an increased breast cancer risk, which may vary by formulation. If confirmed, consideration of the breast cancer risk associated with different oral contraceptive types could impact discussions weighing recognized health benefits and potential risks.
gynecology/breast-health/breast-cancer-riskcontraception/adverse-effects/cardiovascular-effectstherapeutics/hormonal-agents/progesterone-and-progestins
Open Access
Depo-medroxyprogesterone acetate (DMPA) is an injectable contraceptive that contains the same progestin as the menopausal hormone therapy regimen found to increase breast cancer risk among postmenopausal women in the Women's Health Initiative clinical trial. However, few studies have evaluated the relationship between DMPA use and breast cancer risk. Here, we conducted a population-based case-control study among 1,028 women ages 20 to 44 years to assess the association between DMPA use and breast cancer risk. Detailed information on DMPA use and other relevant covariates was obtained through structured interviewer-administered in-person questionnaires, and unconditional logistic regression was used to evaluate associations between various aspects of DMPA use and breast cancer risk. We found that recent DMPA use for 12 months or longer was associated with a 2.2-fold [95% confidence interval (CI), 1.2-4.2] increased risk of invasive breast cancer. This risk did not vary appreciably by tumor stage, size, hormone receptor expression, or histologic subtype. Although breast cancer is rare among young women and the elevated risk of breast cancer associated with DMPA appears to dissipate after discontinuation of use, our findings emphasize the importance of identifying the potential risks associated with specific forms of contraceptives given the number of available alternatives.
Blood and urine specimens from 27 premenopausal breast cancer patients and 62 healthy controls have been compared with respect to concentration of testosterone and progesterone in blood and of testosterone and androstanediol in urine, measured in the luteal phase of the menstrual cycle. There was a strong positive association between the concentration of the two androgens, either in blood or urine, and breast cancer risk. A strong association was also observed with decreasing levels of progesterone. The association was statistically significant (p for trend less than 0.01) for each hormone; the rate ratios were 10.2 for serum testosterone (highest category), 5.6 for serum progesterone (lowest category), 8.4 for urinary testosterone (highest category), and 5.2 for androstanediol (highest category). The rate ratio for women presenting both high serum testosterone and low progesterone was 21.8 (4.1 to 116.1). Considering the exposure to at least one of three androgens at the highest level and low progesterone, the rate ratio was as high as 90.2 (8.2 to 989.7). This study provides evidence for the hypothesis that increased androgenic activity is an important risk indicator for breast cancer, particularly when associated with anovulation, as indicated by low serum progesterone level.
Serum testosterone, progesterone, luteinizing hormone, prolactin, and sex hormone-binding globulin levels were measured in 55 normal controls, in 31 patients with hyperplastic alterations of breast epithelium, and in 23 patients with breast cancer. All patients and controls were premenopausal, and they were comparable for age, weight, and body surface. In the controls, the mean level of testosterone [0.47 +/- 0.16 (S.D.) ng/ml] was lower and the mean level of progesterone (17.63 +/- 8.11 ng/ml) was higher than in breast cancer patients [testosterone level, 0.62 +/- 0.22 ng/ml (p less than 0.005); progesterone level, 11.4 +/- 8.0 ng/ml (p less than 0.005)] and in patients with breast epithelial hyperplasia [testosterone level, 0.55 +/- 0.2 ng/ml (p less than or equal to 0.05); progesterone level, 13.9 +/- 8.6 ng/ml (p less than 0.05)]. No difference was found in the mean circulating levels of luteinizing hormone, prolactin, or sex hormone-binding globulin between controls and patients. These results confirm previous findings of increased urinary testosterone excretion in women with anovulatory menstrual cycles and epithelial hyperplasia or cancer of the breast and strongly support the hypothesis that androgens play an important role in both induction and development of breast cancer.