Mammographic densities as a criterion for entry to a clinical trial of breast cancer prevention.

Nf Boyd,Is Simor,Jc Macdonald,Rk Sparrow,R Jong,E Fishell,V Kriukov,G Lockwood,D Tritchler

doi:10.1038/bjc.1995.358

Abstract

The most convincing evidence that a factor such as dietary fat is causally related to breast cancer would be obtained from a randomised controlled trial in which exposure to dietary fat intake was systematically varied. A limitation of randomised controlled trials of breast cancer prevention, however, is the large sample size required to detect plausible reductions in risk resulting from the intervention. We describe here experience over a period of 9 years with the use of one risk factor for breast cancer as a criterion for entry to a clinical trial of breast cancer prevention. The risk factor used was the presence of extensive densities in the breast tissue on mammography, which has been found by several investigators to be strongly associated with risk of breast cancer. Using this criterion for selection, 1800 subjects of mean age 46 years were enrolled between 1982 and 1986, and again between 1988 and the present. Throughout this period, the point estimate of annual invasive cancer incidence was approximately 6 per 1000 per year. The observed cancer incidence has been consistently 4-5 times the incidence expected from age-specific breast cancer incidence data for women living in Ontario. These data show that the selection of subjects for a clinical trial of breast cancer prevention using the criterion of extensive breast parenchymal densities does identify a group at substantially increased risk of breast cancer. Use of this criterion for the selection of subjects can substantially reduce the sample size required for a clinical trial of a preventive strategy.

Highlights

A limitation of randomised controlled trials of breast cancer prevention, is the extremely large sample size required to detect plausible reductions in risk resulting from the intervention
We describe here experience over a period of 9 years with the use of one risk factor for breast cancer as a criterion for entry to a clinical trial of breast cancer prevention
The risk factor used was the presence of extensive densities in the breast parenchyma on mammography, which has been found by several investigators to be strongly associated with risk of breast cancer (Wolfe, 1976a,b; Saftlas and Szklo, 1987; Oza and Boyd, 1993)

Summary

Selection of subjects

After completing work on the relationship of dense breast parenchyma to breast cancer risk (Boyd et al, 1982a, 1982b), we began in 1982 to recruit women with mammographic parenchymal densities in at least 50% of the breast into a series of trials testing a dietary intervention. Between 1982 and 1986, 295 women with these radiological characteristics were recruited into pilot studies (Boyd et al, 1988), and in 1988 a randomised clinical trial was started to determine if breast cancer incidence could be reduced by the dietary intervention developed in these pilot studies (Boyd et al, 1990) Recruitment for this trial was expanded, and a total of 2040 subjects have been enrolled to date. Estimates of risk from jects entered into the cancer prevention trial since 1988 have subjects in both the pilot studies and the main cancer prevenbeen asked to respond to the same questionnaire admin- tion trial, over the entire period of observation, are identical istered at the clinic visit closest to the anniversary of the date and are both 4.5 times the age-specific risk for the population of randomisation. In addition to contacting all of those in the cancer prevention trial, we have been successful in contacting annually 95% of the 295 subjects from pilot studies and 90% of the subjects who have dropped out of the trial

Characteristics of subjects

Mammographic densities

These findings indicate that the strategy used here to select