Benign Breast Disease May Be Independent Risk Factor for Invasive Breast Cancer

PITTSBURGH—Women with benign breast disease were 54% more likely to develop invasive breast cancer than were women without a diagnosis of benign breast disease, according to an analysis of data from Breast Cancer Prevention Trial (BCPT) of the National Surgical Adjuvant Breast and Bowel Project (NSABP). Lead investigator Jiping Wang, MD, a research associate in biostatistics at the University of Pittsburgh and a statistician for the NSABP, reported that the risk associated with benign breast disease was higher among women age 50 and older.

The overall BCPT study population was 13,388 healthy women who were prospectively followed to determine the effect of tamoxifen treatment on the development of breast cancer. All breast biopsies undertaken during the trial were systematically reported, providing a good opportunity to examine the relationship between benign breast disease and invasive breast cancer, Dr. Wang said.

Benign Disease Diagnoses

The current study population was 11,307 women who were selected from the overall BCPT population because they did not have a history of atypical hyperplasia or in situ cancer. Benign breast disease diagnoses were derived from pathology reports from participating institutions and consisted of adenosis, cyst, duct ectasia, fibrocystic disease, fibroadenoma, fibrosis, hyperplasia, metaplasia, and papilloma. All benign breast disease diagnoses were made after randomization in the BCPT study and prior to the diagnosis of invasive breast cancer. The study time period was April 1992 through March 1998.

During the study, 1,301 women received a diagnosis of benign breast disease, and 29 went on to develop invasive breast cancer. Among the 10,006 women who did not have a benign breast disease diagnosis, 193 developed breast cancer. That made the annual rate of invasive breast cancer 8.42/1,000 women with benign breast disease, compared to 4.47/1,000 for women without benign breast disease (relative risk: 1.78).

When the researchers analyzed the data according to age, women with benign breast disease who were age 49 or younger had an annual rate of invasive breast cancer of 5.85/1,000 vs 4.61/1,000 for women without benign breast disease (relative risk: 1.24) For women age 50 and older, those with benign breast disease had an annual rate of invasive breast cancer of 12.18/1,000 vs 4.39/1,000 for those without the benign breast disease diagnosis (relative risk: 2.58).

Invasive Disease Risk

The investigators then analyzed the risk of invasive breast cancer by both benign breast disease diagnosis and treatment group (tamoxifen vs placebo). For women with benign breast disease, the annual rate of invasive breast cancer was 10.40/1,000 in the placebo group vs 5.91/1,000 in the tamoxifen group. Among women without benign breast disease, the annual rate of invasive breast cancer was 5.71/1,000 in the placebo group vs 3.28/1,000 in the tamoxifen group.

"When we stratified by treatment arm, we found that the relative risks of breast cancer for women with and without benign breast disease are quite similar across treatment arms," Dr. Wang said. "They are 1.69 vs 1.73 in the placebo and tamoxifen arms, respectively."

The researchers then performed a multivariate analysis to answer the question: Is the increased risk due to the benign breast disease itself, or do more women with benign breast disease also have a family history of breast cancer or other breast cancer risk factors?

After adjusting for treatment and the predicted 5-year risks from the Gail model, they found that benign breast disease is a significant independent risk factor for invasive breast cancer, with a relative risk of 1.54.

Among women who developed breast cancer during the study, a diagnosis of benign breast disease was not significantly associated with estrogen receptor status or nodal status, but did predict for larger tumors. Forty-percent of women with benign breast disease had tumors larger than 2 cm, compared to 17% for women without benign breast disease.