As noted above we conducted a study to determine whether the risk of breast cancer associated with oral contraceptive (OC) use is higher in women with BRCA1/BRCA2 mutations than in other women by examining whether breast cancer patients with these mutations were more likely than breast cancer patients without mutations in BRCA1/BRCA2 to have used OCs. We tested for BRCA1 185delAG and 5382insC and BRCA2 6174delT mutations in a population-based sample of 50 young Ashkenazi Jewish breast cancer patients. Nine patients (18%) had a BRCA1 mutation, and five patients (10%) had a BRCA2 mutation. Long-term OC use (>48 months) before a first full-term pregnancy was associated with an elevated risk of being classified as a mutBRCA carrier (odds ratio = 7.8; trend, P = 0.004). The results suggested that OC use may increase the risk of breast cancer more in mutBRCA carriers than in noncarriers. It was the first published example of gene x environment interaction related to one of the breast cancer major locus susceptibility genes. As noted above we have secured funding to pursue this and other gene x environment interactions with these breast cancer genes.

Hormone replacement therapy (HRT) is one of the most popular categories of prescription medications in the United States. Few data exist on the association between combination hormone replacement therapy (CHRT), i.e., adding a progestin to estrogen for all or part of a monthly cycle. We recently reported results from a population-based case-control study of breast cancer in Los Angeles designed to evaluate this relationship. Information on 1,897 postmenopausal cases and 1,637 postmenopausal controls aged 55-72 was analyzed. HRT was associated with a 10% higher breast cancer risk for each five years of use (odds ratio per five years of use = OR5 = 1.10, 95% confidence interval (CI) = 1.02-1.18). Risk was substantially higher for CHRT use (OR5 = 1.24, 95% CI = 1.07-1.45) than for ERT use (OR5 = 1.06, 95% CI = 0.97-1.15). Risk estimates were substantially higher for sequential estrogen-progestin therapy (SEPRT), in which an estrogen alone is given for part of a monthly cycle followed by estrogen-progestin in combination (OR5 = 1.38, 95% CI = 1.13-1.68) than for continuous combined therapy (CCRT), in which estrogen and progestin are given together each day of use (OR5 = 1.09, 95% CI = 0.88-1.35). This study provided strong evidence that the addition of a progestin to HRT enhances markedly the risk of breast cancer relative to estrogen use alone.

Since 1994, we have conducted three other case-control studies of breast cancer among Asian-Americans in Los Angeles County. The first study was designed to investigate the role of soy, and other dietary and non-dietary risk factors in explaining the increase of breast cancer incidence in Asians upon migration to the west. Data collection for the first study (including 350 cases and 350 controls) was completed in May 1999. Preliminary results show that high soy intake may protect against breast cancer. The second study is an expansion of the first study to achieve a larger sample size and to include environmental exposures such as polycyclic aromatic hydrocarbons and heterocyclic amines and their metabolizing genes in our investigation. In January 2000, we will begin data collection for the third case-control study which is a further expansion of the above breast cancer studies in Asian-Americans. The main objectives of the third study are to refine our characterization of the role of soy and to investigate candidate estrogen metabolism genes in the etiology of breast cancer. To understand the mechanism(s) by which soy foods may influence the risk of breast cancer, we have completed a seven month soy intervention study in 20 healthy, normal cycling premenopausal women. In brief, we observed a statistically significant 9% reduction in serum luteal phase estradiol levels in association with three months of soy food supplementation. Participants added 32 mg of isoflavones to their daily diet during the intervention period (the usual intake of isoflavones in Asia is between 20-40 mg per day). We have just received funding to conduct a dietary intervention study in postmenopausal women.

Despite decades of use, the long-term safety of breast implants in women remains a concern. We abstracted the records of 3,182 white women who received cosmetic breast implants between 1953 and 1980. Cancer outcomes through 1991 have been ascertained through record linkage with the Los Angeles Cancer Surveillance Program. With a median follow-up of 14.4 years, 31 breast cancers were observed, compared with 49.2 expected (SIR=63%, 95% CI: 43%, 90%). The distribution of stage of disease at diagnosis did not differ from that of all similar breast cancer patients in Los Angeles County.