Epidemiology and Pathologic Precursors

Relatively few large epidemiologic studies have evaluated breast cancer risk factors according to the ER status of the tumor. Age-specific incidence rates of breast cancer vary according to ER status: the age incidence curve for ER+ tumors slows substantially at menopause whereas the rate continues to rise steadily for ER- tumors. Endogenous hormonal variables (menarche, parity, age at first birth, body mass index) have been evaluated in several recent studies. Reproductive factors have tended to be most strongly related to ER+ tumors among postmenopausal women differences for BMI have been inconsistent and differences in premenopausal women have infrequently been addressed. In two previous studies, family history was more strongly associated with ER- tumors although in a third this was true only when relatives were diagnosed before age 45. This may in part be due to the finding that while BRCA1-associated tumors are for the most part ER-, BRCA2-associated tumors are often ER+. Physical activity was related in comparable manner to both ER+ and ER- tumors in one study.

Although increasing evidence suggests that estrogen plus progestin hormone replacement therapy increases breast cancer risk more than estrogen use alone, no previous study to our knowledge has evaluated these relationships by ER status of the tumor. Similarly, although proliferative benign breast disease is a well-established risk factor for breast cancer, the relation between ER status of both the benign lesion and the subsequent invasive cancer has not previously been addressed. Circulating levels of estradiol in postmenopausal women have been consistently and strongly associated with an increased risk of breast cancer though the relation to ER status is unknown. Plasma testosterone, prolactin and insulin-like growth factor I (IGF-1) have been positively associated with breast cancer risk, but no previous study has reported these relations by ER status of the tumor. Thus there has been little progress in defining the risk factors related specifically to the development of ER- breast cancer.

We propose to draw on the existing data from the ongoing Nurses' Health Study (G. Colditz, PI. CA 87969) and sub-studies that relates histologic subtypes of benign breast disease to subsequent risk of breast cancer in the cohort (G. Colditz PI CA 46475) and that evaluate several endogenous hormones in relation to breast cancer risk (S. Hankinson PI, CA49449). We will reevaluate existing data to relate exposure information to risk of ER- tumors to determine if risk factors differ between these subtypes of breast cancer. Specifically we will test the following hypotheses

Markers of endogenous hormones (e.g., age at first birth, parity, age at menarche, physical activity) and endogenous hormones themselves (i.e., estradiol, testosterone) are more strongly related to ER+ tumors while family history of breast cancer and IGF-I are more strongly related to ER- tumors.

Use of estrogen alone increases risk of ER+ tumors, but estrogen plus progestin promotes cell division and increases risk of ER- tumors (i.e. the proportion of ER- tumors is higher among E plus P users compared to E alone).

ER+ benign lesions increase the risk preferentially of ER+ tumors and ER- benign lesions increase the risk preferentially of ER- tumors

Graham A. Colditz, M.D., Dr. P.H.-Dr. Colditz is a Professor of Medicine, Brigham and Women's Hospital, Harvard Medical School and a Professor of Epidemiology, Harvard School of Public Health (http://www.hsph.harvard.edu/facres/cldtz.html). He is the Principal Investigator of the Nurses' Health Study. He will serve as a co-investigator on Project 1. Email: Graham.colditz@channing.harvard.edu

Susan E. Hankinson, Ph.D.-Dr. Hankinson is an Associate Professor of Medicine, Brigham and Women's Hospital, Harvard Medical School and an Associate Professor of Epidemiology, Harvard School of Public Health. She is a co-investigator of the Nurses' Health Study. She is an expert in the epidemiology of breast cancer. She will serve as a co-investigator on Project 1. Email: Sue.hankinson@channing.harvard.edu

Stuart J. Schnitt, M.D.-Dr. Schnitt is Associate Professor of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School and Associate Director of Anatomic Pathology, Beth Israel Deaconess Medical Center. He is an expert in breast cancer pathology. He will serve as a co-investigator on Project 1 and a collaborator on Project 4. Email: Sschnitt@bidmc.harvard.edu

The Nurses' Health Study cohort was defined when 121,700 women returned a mailed questionnaire in 1976. The study population consisted of female, registered nurses, 30 to 55 years of age at that time, who were identified in 1972 as married and residing in one of eleven states in the U.S. by the state boards of nursing and the American Nurses' Association. The cohort is followed through biennial mailed questionnaires and document breast cancers and other illnesses by medical records within cores of the ongoing program project. The National Death Index is searched to complete the follow-up of mortality. As of the 1998 follow-up cycle, participation has remained >90%. In 1989-90, blood samples were collected from 32,826 members of the cohort. These samples were centrifuged, separated into plasma, RBC, and buffy coat components and have been archived in nitrogen freezers since collection. A large number of nested case-control studies have been conducted evaluating biomarker/breast cancer relationships.

Nurses' Health Study
SEER
ACS Cancer Statistics

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