SAN ANTONIO — A reduction in mammographic breast density after 12–18 months of tamoxifen use—prescribed for primary prevention of breast cancer—is an excellent early predictor of subsequent treatment efficacy, according to a new report from the landmark International Breast Intervention Study I.
Women who showed at least a 10% decrease in breast density by visual assessment on routine mammography 12–18 months into their 5-year course of tamoxifen experienced a 63% reduction in breast cancers compared with placebo through 8 years of follow-up in IBIS-I, Jack Cuzick, Ph.D., reported at the San Antonio Breast Cancer Symposium.
“This is the first time in cancer we've found a biomarker that predicts response to preventive treatment. … The point is, if your preventive intervention doesn't work, there's no point in pressing on for 5 years,” explained Dr. Cuzick, chairman of the IBIS-I steering committee and head of the Cancer Research UK Centre for Epidemiology, Mathematics, and Statistics, London.
Many healthy women at high risk for breast cancer are reluctant to take tamoxifen because of concerns about toxicity. The new IBIS-I findings have the potential to increase adoption of tamoxifen therapy in eligible women because after just 12–18 months they'll have a good indication of whether it's working for them.
IBIS-I randomized 7,154 women at high risk for breast cancer to 5 years of tamoxifen or placebo. At the latest follow-up, the tamoxifen group had a significant 27% decrease in breast cancer risk (J. Natl. Cancer Inst. 2007;99:272–82).
The new mammographic density analysis included 126 IBIS-I participants who developed breast cancer after their 12- to 18-month mammogram and 942 controls who remained free of breast cancer during the first 5 years of the study. At baseline, 47% of the women had at least 50% of their breasts covered by densities.
Among the roughly 40% of tamoxifen-treated subjects who showed at least a 10% reduction in breast density at their 12- to 18-month mammograms, there was a 63% reduction in breast cancer risk compared with placebo after adjustment for age, body mass index, and baseline breast density. In contrast, tamoxifen-treated women who did not have at least a 10% reduction in breast density went on to have essentially the same breast cancer incidence as did those on placebo.
In an analysis restricted to participants with baseline atypical hyperplasia or lobular carcinoma in situ, a 10% or greater decrease in breast density in response to tamoxifen was associated with a 71% reduction in breast cancer risk compared with placebo, Dr. Cuzick continued.
“Mammographic density is a very simple thing to measure that really isn't very much used at the moment,” he noted in an interview. Visual estimates of breast density to the nearest 5% as employed in IBIS-I show “very good” reproducibility, Dr. Cuzick added.
Multiple studies have established that baseline breast density has the highest attributable risk of all known breast cancer risk factors. In an earlier IBIS-I analysis, a baseline density of 51%–75% was an independent risk factor associated with a 2.7-fold increased risk of breast cancer, while a density in the 76%–100% range conferred a 3.9-fold increased risk.
Dr. Cuzick stressed that the new findings apply specifically to tamoxifen for prevention. Whether the same holds true for tamoxifen in the adjuvant setting in women being treated for breast cancer remains to be seen.
Dr. Cuzick is now looking at the ongoing IBIS-II trial database to learn whether early change in breast density is also a predictor of efficacy for the aromatase inhibitor anastrozole (Arimidex) when used for primary prevention in high-risk postmenopausal women. It will also be important to scrutinize mammograms collected in the clinical trials that led to approval of raloxifene (Evista) for breast cancer prevention in high-risk women to determine whether change in breast density is predictive of efficacy for that drug as well.
“If this turns out to be a general phenomenon that applies to any kind of preventive activity, it might mean we can begin to evaluate breast cancer preventive strategies in trials of 1–2 years rather than 10 years to find out if something works,” Dr. Cuzick said.
Dr. Cuzick said he has no financial conflicts of interest regarding the study.
'This is the first time in cancer we've found a biomarker that predicts response to preventive treatment.' DR. CUZICK