ER Status Predicts Response to Tamoxifen in DCIS Patients

SAN ANTONIO—A retrospective analysis of data from the National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-24 suggests that estrogen-receptor (ER) expression predicts response to tamoxifen (Nol-vadex) among patients with ductal carcinoma in situ (DCIS).

Speaking at the 25th Annual San Antonio Breast Cancer Symposium (abstract 30), D. Craig Allred, MD, professor of pathology, Baylor College of Medicine, reported that tamoxifen treatment was associated with an approximate 50% reduction in the risk of subsequent breast cancer among ER-positive patients, compared with placebo, but had little benefit among those who were ER negative.

Study Population

The study group was drawn from the original B-24 trial, which randomized 1,804 patients with DCIS to lumpectomy and local radiation plus either tamoxifen or placebo. In the original trial, the use of tamoxifen was associated with a 37% reduction in all breast cancer events at 5 years. Estrogen-receptor status was not a prerequisite for enrollment in the B-24 trial.

In the current study, researchers from Baylor and the NSABP evaluated tamoxi-fen response among all women with known receptor status in the B-24 trial. ER results were available on a subset of 676 patients—344 in the placebo group and 332 in the tamoxifen group.

Estrogen-receptor results for 450 of the patients had been determined in a central reference laboratory using a standardized immunohistochemistry method. The remaining 226 results were obtained from outside laboratories and were determined primarily by immunohistochemistry procedures. However, differences were apparent in the sensitivity of the various assays used by the outside laboratories (see discussion below).

In the study population overall, 23% of the tumors were ER negative, and 77% were ER positive. In the tamoxifen group, 20% were ER negative, and 80% were ER positive. Among patients in the placebo group, 25% had ER-negative tumors, and 75% had ER-positive tumors. These differences were not statistically significant, Dr. Allred said.

Similarly, no significant differences were noted between the two arms in the distribution of several other variables that might influence outcome, including tumor size, surgical margins, comedo necrosis, and patient age.

When the investigators analyzed patient outcome according to receptor status and tamoxifen treatment, they found little advantage to tamoxifen in the patients with ER-negative tumors. At a median follow-up of 8.7 years, the percentage of ER-negative women who had experienced subsequent breast cancer was 23% in the tamoxifen-treated group and 26% in the placebo group.

In contrast, among ER-positive women, the percentage of breast cancer events was 10% in the tamoxifen group, compared with 23% in the placebo group—about a 50% reduction for ER-positive women treated with tamoxifen.

"The Kaplan-Meier curves for time to first breast cancer event show that 90% of tamoxifen-treated women with ER-positive DCIS were disease free at 9 years," Dr. Allred said, "compared with 70% to 80% of those in the other groups. This again emphasizes the benefit of tamoxifen in ER-positive disease."

In formal statistical analyses of results, ER-positive patients treated with tamoxi-fen had a relative risk of subsequent breast cancer of 0.41, a highly significant 59% reduction (P = .0002). Among ER-negative women, the relative risk was 0.80—a 20% risk reduction that was not significant (P = .51).

Effect of Different Assays

"The trend for an apparent benefit from tamoxifen in ER-negative DCIS is puzzling," Dr. Allred said. "A comparison of ER results between the central and outside laboratories may shed some light on this issue."

The central reference laboratory used in the study relied on a standardized assay that had been validated as useful in predicting response to hormonal therapy in several published studies of invasive breast cancer. Results from the
central laboratory showed that 20% of the tumors were ER negative. However, the negative rate from the outside labs was 30%, or 50% higher.

"Studies assessing ER status by immunohistochemistry in invasive breast cancer have shown that the false-negative rate can be fairly high in laboratories using diverse assays that have not been standardized or validated, and the same may be true for DCIS," Dr. Allred said. "This idea is supported by comparing the clinical results from outside laboratories in this study to results from the central laboratory."

When the researchers restricted their analysis to the ER-negative results determined only in the outside laboratories, tamoxifen appeared to reduce subsequent breast cancer by 57% in "ER-negative" DCIS. But an analysis restricted to ER-negative results obtained from the central reference laboratory found "absolutely no benefit" to tamoxifen in ER-negative DCIS.

"It is likely that the ER-negative group defined by outside laboratories contained many false-negative results—up to 50%—giving a false impression of response to tamoxifen," Dr. Allred said. "This type of error results from tests with insufficient sensitivity. This is a danger because most physicians probably would not give tamoxifen to patients with ER-negative DCIS, denying those with false-negative results a chance of benefiting from the drug."