ASCO Breast: Aromatase Inhibitor Reverses Genetic Marker of Breast Cancer Risk

SAN FRANCISCO, Sept. 11 -- Anastrozole (Arimidex), an aromatase inhibitor, appears to reverse gene methylation, a marker of malignancy risk, in breast cancer.

When given as adjuvant therapy, anastrozole seems to have its effect in the contralateral breast, supporting a benefit in chemoprevention, researchers said at the American Society of Clinical Oncology Breast Cancer Symposium.here.

After six months of anastrozole, hypermethylation decreased in more than half of contralateral breast tissue samples across the six genes measured in women at high risk for a second malignancy, reported Tatiana M. Prowell, M.D., of Johns Hopkins, and colleagues, in a pilot study.

The overall 1.3-unit cumulative absolute decline in methylation was not significant (P=0.08), but more substantial decreases were seen in RASSF1a and Twist genes (P=0.01 and P

So the researchers tested whether methylation could measure changes related to this benefit.

Their prospective, single-arm study included 47 postmenopausal women with a recent diagnosis of hormone receptor positive breast cancer who had completed local therapy and received anastrozole at a dose of 1 mg daily for one year.

At baseline, 36 women had an optional contralateral breast biopsy. At six months, 34 had another biopsy for a total of 33 matched pairs. These tissue samples were used to measure methylation of six genes by quantitative multiplex methylation-specific PCR.

The researchers found that gene hypermethylation was common in the contralateral breast in these high-risk women. Among them, 84% had at least one unit of cumulative methylation in the six-gene panel at baseline.

There was methylation in 10 of 29 RAR-beta genes measured, nine of 27 measured for Twist, nine of 32 measured for RASSF1a, five of 29 measured for Cyclin D2, five of 32 measured for APC1, and four of 29 measured for Hin1.

Most of these individual genes were more likely to decrease than increase in methylation by six months. The cumulative methylation index was decreased in 48% of tissue samples and increased in 28% whereas 24% showed no change.

RASSF1a and Twist showed the greatest reductions in methylation (25% and 33% decreased, respectively) with the fewest increases (6% and 15%, respectively).

Only one gene showed the opposite trend with 24% of samples increasing in Cyclin D2 methylation whereas just 7% decreased in Cyclin D2 methylation.

Among the subset of patients with methylation at baseline in their contralateral breast, the median absolute changes were:

• A decrease of 6.3 methylation units for RASSF1a (P=0.01).
• A decrease of 4.5 methylation units for Twist (P