Continuous HRT Increases Risk of Lobular But Not of Ductal Breast Cancer

Laurie Barclay, MD

December 03, 2002

Dec. 3, 2002 — Continuous hormonal replacement therapy (HRT) is associated with an increased risk of lobular breast cancer but not of ductal carcinoma, according to the results of a multicenter case-control study published in the Dec. 15 issue of Cancer (the study was available online Dec. 3).

"The incidence of invasive lobular carcinoma has been increasing among post-menopausal women in some parts of the U.S," writes Janet R. Daling, PhD, from the Fred Hutchinson Cancer Research Center in Seattle, Washington, and colleagues. "Part of this may be due to changes in classification over time. However, the use of combined estrogen and progestin HRT has also increased during the last decade and may account in part for the increase in invasive lobular breast cancer."

This study used data from the NICHD Women's Contraceptive and Reproductive Experiences (CARE) Study, a large case-control breast cancer study of white and African-American women. The investigators conducted in-person interviews of 1,749 postmenopausal women diagnosed with their first invasive breast tumor before the age of 65 years, and compared their responses with those of 1,953 postmenopausal controls identified through random digit dialing.

History of use of unopposed estrogen therapy was not associated with an increase in risk of any histologic type of breast cancer. Women currently using combined HRT had twice the risk of invasive lobular breast cancer (odds ratio [OR], 2.2; 95% confidence interval [CI], 1.4-3.3) and of breast cancer of other histologies combined (OR, 1.9; 95% CI, 1.0-3.4). Although the increase in risk was greater for mixed lobular-ductal than for the pure lobular type, this difference was not statistically significant.

Women who used continuous combined HRT (more than 25 days per month of progestin) for at least five years appeared to be at greater risk of lobular breast cancer (OR, 2.5; 95% CI, 1.4-4.3) than those who used sequential HRT (fewer than 25 days per month of progestin (OR, 1.5; 95% CI, 0.8-2.6). Use of combined HRT was not associated with risk of ductal breast cancer.

"Post-menopausal women who take combined HRT appear to be at an increased risk of lobular breast cancer," the authors write. "Data from this study suggest that neither unopposed estrogen-HRT use nor combined HRT substantially increase the risk of ductal breast cancer among women less than 65 years of age."

Study limitations include potential bias resulting from limited numbers of interviews of all eligible cases and from limited screening and phone interviews of potential controls; reliance on accurate history concerning HRT use; lack of pathology review of the tumors to ensure a consistent assessment of histology; and lack of generalizability of the findings to women older than age 65 who may have used HRT for longer durations.

"Evidence is mounting regarding the adverse effects of adding progestin to HRT in regards to breast cancer risk," the authors write. "Further studies are needed that address breast cancer risk associated with combined HRT by histologic type as well as the number of days progestin is administered. Since the use of continuous progestin therapy is relatively recent, studies in older women who have used combined HRT for long durations will be important."

A separate study, reported in the December issue of Obstetrics and Gynecology, agrees with these findings. The multicenter case-control study analyzed data from 3,823 postmenopausal white and African-American women aged 35 to 64 years. They found the risk for breast cancer associated with using continuous combine HRT for more than 5 years was 1.54 (95% CI, 1.10-2.17). There was no association with other hormone therapies, including estrogen only and sequential combined. Investigators also found that the risk dissipates quickly when therapy is discontinued.

Cancer. 2002;95:2455-2464
Obstet Gynecol. 2002;100:1148-1158

Reviewed by Gary D. Vogin, MD

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