defined). If oral contraceptives interact with susceptibility, the increased risk should be observable in this restricted population.

An alternative strategy derived from a large case-control study might use the same criteria for identifying susceptible cases but use phenotypically normal sisters as controls. Ideally, a genetic analysis (e.g., restriction fragment length polymorphism) of both case and control subjects would be performed to detect specific molecular alterations. In addition, or alternatively, linkage analyses could be done.

Molecular markers for mutational effects (i.e., oncogene activation), loss of heterozygosity, or polymorphisms (i.e., alleles) can be sought, given the availability of appropriate assays. One such study of traditional case-control design is currently in progress, funded by the National Cancer Institute. Rare alleles of Ha-ras are being sought as susceptibility markers with oral contraceptives being considered as effect modifiers (Garrett and Hulka, personal communication).

One innovative strategy (Swift et al., 1990) tests hypothesized associations between a candidate allele, for which there is a specific laboratory test, and a common chronic disease, such as breast cancer. Families in which this allele is segregating are identified through index individuals who are heterozygous or homozygous for the allele. One relative with the disease of interest (e.g., breast cancer) must be available for each index case. The proportion of heterozygotes observed in the diseased sample is compared with the expected proportion, based on each diseased relative's null probability. The advantage of this strategy over a more traditional case-control approach is the reduction in sample size required to test the hypothesis of a specific allele rendering susceptibility to breast cancer.

To enhance the capability of molecular epidemiological research, the molecular characterization of breast cancer in oral contraceptive users and nonusers is needed. If polymerase chain reaction can be used and restriction fragment length polymorphisms can be studied using formalin-fixed tissues, existing repositories of tumor samples (i.e., clinical pathology laboratories) could provide expanded opportunities for these studies (Frye et al., 1989; Resnick et al., 1990). Whatever study design and epidemiological strategy are used, every attempt should be made to observe the influence of oral contraceptive use on specific types of malignant breast tumors, using the best generally available technology.

Estrogen Metabolism

Estrogen metabolism may figure prominently in future epidemiological research. Fishman and colleagues (1984) have proposed that breast cancer patients, in comparison with normal controls, have higher



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