Ten- to fourteen-year effect of screening on breast cancer mortality.

Results from the randomized trial conducted by the Health Insurance Plan (HIP) to determine the efficacy of breast cancer screening with mammography and palpation are reported for longer periods than previously available. By the end of 10 years after entry, the study group's mortality due to breast cancer was about 30% below the control group's. Arithmetic gains due to screening were maintained through year 14; relative gains declined. With increases in the period of follow-up, cumulative survival rates among cases detected by mammography alone (palpation negative during screening), decreased more rapidly than rates among other subgroups, but survival rates for mammography cases remained relatively high. Study women aged 40-49 years at entry began to show lower breast cancer mortality than those in the control group as duration of follow-up increased. Reservations are advanced about the acceptance of this finding as evidence of the efficacy of screening under age 50 under the conditions of the HIP study. The reservations are based on the observation that the decrease of mortality among the study group aged 45-49 at entry is concentrated entirely among cases diagnosed after they reached 50 years of age.

A prospective study of endogenous estrogens and breast cancer in postmenopausal women.

BACKGROUND: Circumstantial evidence links endogenous estrogens to increased risk of breast cancer in women, but direct epidemiologic support is limited. In particular, only a few small prospective studies have addressed this issue. PURPOSE: Our purpose was to assess breast cancer risk in relation to circulating levels of the two major endogenous estrogens, estrone and estradiol, measured before the clinical onset of the disease. METHODS: The association between serum levels of estrogens and the risk of breast cancer was examined in a prospective cohort study of 14,291 New York City women, 35-65 years of age, who received screening for breast cancer at the time of blood sampling and who had not been diagnosed with breast cancer. During the first 5 1/2 years of study, we identified 130 breast cancers among the postmenopausal group (7063 women, 35,509 person-years). The case subjects and twice as many postmenopausal control subjects were included in a case-control study nested within the cohort. Biochemical analyses for percent free estradiol, percent estradiol bound to sex hormone-binding globulin (SHBG), total estradiol, estrone, and follicle-stimulating hormone were performed on sera that had been kept at -80 degrees C since sampling. RESULTS: For increasing quartiles of total estradiol, the odds ratio (ORs) of breast cancer, as adjusted for Quetelet index (weight in kilograms divided by the square of the height in meters), were 1.0, 0.9, 1.8, and 1.8 (P value for trend = .06); the ORs for increasing quartiles of estrone were 1.0, 2.2, 3.7, and 2.5 (P value for trend = .06). For increasing quartiles of free estradiol, defined as the fraction of estradiol that is not bound to proteins, the Quetelet index-adjusted ORs of breast cancer were 1.0, 1.4, 3.0, and 2.9 (P value for trend < .01). When we considered the percent of estradiol bound to SHBG, the Quetelet index-adjusted ORs were 1.0, 0.70, 0.40, and 0.32 (P value for trend < .01), thus suggesting a strong protective effect. These associations persisted or became even stronger when analyses were restricted to women whose samples had been drawn 2 or more years before breast cancer diagnosis. CONCLUSIONS: These data represent the first confirmation in a large prospective epidemiologic study of a link between circulating estrogens and breast cancer risk. Although estrogen levels appeared to fall within the conventional limits of normality in all women under study, those who subsequently developed breast cancer tended to show higher levels of estrone, total estradiol, and free estradiol, and a lower percent of estradiol bound to SHBG than women who remained free of cancer. IMPLICATIONS: Factors that increase endogenous estrogen production or reduce the binding of estradiol to SHBG may increase a woman's risk of developing breast cancer later in life.

Epidemiology of minimal breast cancer among women screened in New York City.

A case-control study based on a screened population in New York City examined epidemiologic risk factor differences between minimal breast cancer (in situ and small invasive carcinomas) and all other breast carcinomas, referred to as clinical breast cancer. Histopathologic re-review of the original slides identified 113 minimal and 792 clinical breast cancers among 1,290 eligible cases; 2,173 randomly selected screenees served as controls. Among those who developed cancer, black women were twice as likely to develop minimal, as compared to clinical, breast cancer. Women who were less than 20 years of age at first live birth had more than double the probability of being diagnosed with minimal breast cancer, whereas women with first live birth at age 30 years or greater and nulliparous women were at 1.5 times the risk of clinical breast cancer. The relative proportion of minimal breast cancer increased with increasing number of children breast fed, being twofold among women who nursed 2 children or more. Unlike clinical breast cancer, minimal breast cancer was not associated with either family history of breast cancer or obesity. Meaningful histologic differences were not apparent between the case subgroups. Except possibly for obesity, these results could not be explained by any plausible diagnostic bias.

Endogenous estrogens and risk of breast cancer by estrogen receptor status: a prospective study in postmenopausal women.

A positive association between postmenopausal serum levels of total estradiol, percentage of free estradiol, and percentage of estradiol not bound to sex hormone-binding globulin (SHBG) and breast cancer risk was recently reported by the New York University Women's Health Study (P. Toniolo et al., J. Natl. Cancer Inst., 87: 190-197, 1995). Data from this prospective study are used to assess whether the observed associations differ according to estrogen receptor (ER) status of the tumor. Between 1985 and 1991, 7063 postmenopausal women donated blood and completed questionnaires at a large breast cancer screening clinic in New York City. Before 1991, 130 cases of first primary breast cancer were identified by active follow-up of the cohort. For each case, two controls were selected, matching the case on age at first blood donation and length of storage of specimens. Biochemical analyses were performed on sera that had been stored at -80 degrees since sampling. ER information was abstracted from pathology reports. Separate statistical analyses were conducted of ER-positive, ER-negative, and ER-unknown groups (53, 23, and 54 matched sets, respectively). In each of the 3 groups, the mean estradiol and the mean percentage of free estradiol were greater (21-28% and 6-7%, respectively) in cases than in controls. Conversely, the mean percentage of estradiol bound to SHBG was 9-12% lower in cases than in controls. The logistic regression coefficients measuring the strength of the association between estradiol and its free and SHBG-bound fractions and breast cancer risk were similar in the ER-positive, ER-negative, and ER-unknown groups. These data suggest that in postmenopausal women, the association of endogenous estrogens with breast cancer risk is independent of the ER status of the tumor. This result is more compatible with the hypothesis of a progression from ER-positive to ER negative tumors than with the hypothesis that ER status identifies two distinct types of breast cancer.

Reliability of measurements of total, protein-bound, and unbound estradiol in serum.

Estradiol (E2) circulates in the blood in three states: unbound (U-E2), bound to sex-hormone binding globulin (SHBG-E2), and bound to albumin. There is evidence to support the concept that only U-E2 and albumin-bound E2, are bioavailable (i.e., rapidly extracted by tissues). A case-control study nested within a large cohort of women, in which we are examining the effect of estrogens on breast cancer risk, offered the opportunity to assess the reliability of measurements of E2, the percentage of SHBG-E2, and the percentage of U-E2 based on multiple annual serum specimens. Long-term (1-2 year) reliability, as estimated by the intraclass correlation coefficient, was assessed in a subgroup of 71 premenopausal and 77 postmenopausal controls for whom two or three serum specimens were assayed. In postmenopausal women the intraclass correlation coefficient for a single measurement of total E2 was only 0.51. As for the percentage of SHBG-E2, intraclass correlation coefficients were 0.83 and 0.94, and for U-E2, 0.72 and 0.77 in the premenopausal and postmenopausal groups, respectively. These data suggest that, whereas single determinations of total E2 are insufficient to reliably estimate a woman's true mean level, a single measurement of the percentage of SHBG-E2 or U-E2 is adequate to assess bioavailability of E2 in an epidemiological study, irrespective of day of the menstrual cycle.

Utilization of diagnostic techniques for cancer of the breast - early diagnosis.

Early diagnosis of breast cancer is the only method with proven potential for lowering the death rate from the disease. Early diagnosis means, in a practical way, detection of preclinical cancer - finding the cancer before it would ordinarily be detected in the normal course of events. This involves mass screening of apparently well women.

Imaging of the breast. A perspective.

It is generally agreed that inspection and palpation of the breast are often inadequate for detection and diagnosis of breast abnormalities. Imaging of the breast, using physical modalities in addition to clinical examination, is important for several reasons, which are discussed in this article.

Effects of news events on response to a breast cancer screening program.

An opportunity to examine the effects of significant, widely reported events on participation in a breast cancer screening program was presented when countrywide public attention was called to breast cancer by reports of the breast surgery of the wives of President and Vice President of United States. These events occurred in September and October 1974 while a breast cancer screening program was underway in the health Insurance Plan of Greater New York. The research design of this program permitted measurements to be made of the participation of the plan's members in the screening before, during, and after these famous mastectomies and of the participants' characteristics during different periods of the research program. In late 1974, when there was great mass media emphasis on breast cancer, participation rates in the breast cancer screening program increased significantly. In the study periods immediately following, however, participation rates declined to previous levels. The increase in Participation rates in late 1974 was fairly uniform among all demographic groups, whether classified by age, education, income, race, or religion. In addition to increases in the participation rate associated with the events of late 1974, there was also an increased tendency among women who were screened to respond readily to mailed invitations to appear for screenings. This increase insensitivity to efforts to win their participation was more pronounced among those groups that this study and other studies have shown are more likely to participate in preventive health programs and to respond more readily to request to participate.

Imaging. Follow-up of breast cancer reconstruction cases.

Imaging a breast that has had cancer and been reconstructed has inherent problems, mostly because the reconstruction and the implant may be obscuring recurrence. It should, therefore, be emphasized that such patients require frequent follow-up. Perhaps every 6 months they also need skillful palpation as well as mammography with proper techniques that image as much of breast tissue as possible with the implant displaced as much as possible.

Strategy (motivation) for detection of early breast cancer.

For successful strategy to increase motivation for mass screening for detection of early breast cancer, three elements are needed: 1) women at risk must be taught the necessity of the examination; 2) they must be made aware of the existence of the facility, which must be made easily accessible; and 3) they must be reassured that the examination is simple, effective, and safe. Mass screening for breast cancer is the only proven method that has the potential to reduce the stationary death rate from the disease. Until true primary prevention is developed, it is necessary to make mass screening ever more efficient, economical, and safe. At the same time, increasing efforts must be made to motivate women to accept such mass screening.

Physical methods in breast cancer diagnosis.

Physical methods in differential diagnosis of breast cancer are important for early detection of the disease in order to prevent delay in treatment and unnecessary surgical procedures. This is particularly true of mammography, which is unique in being able to detect nonpalpable cancer. The importance of this fact lies in the results of the Health Insurance Plan of Greater New York study in which early detection has led to substantial long-term reduction in mortality. The commotion over risk of mammography has resulted in the exaggeration of a minute risk and the minimization of a great potential benefit. Other physical methods, such as thermography, ultrasonography and diaphanography, may be useful in making a diagnosis more definite and, occasionally, in reducing the number of so-called "interval" cancers discovered subsequent to screening or physical examination.