Randomized pre-operative study of 750 mg of fulvestrant and 20 mg tamoxifen in premenopausal women with estrogen receptor-positive breast cancer

INTRODUCTION: Fulvestrant is a pure antioestrogen that has been shown to be as effective as anastrozole in postmenopausal women with hormone receptor-positive breast cancer who have progressed or recurred on tamoxifen. A small pre-operative pilot study of fulvestrant at a dose of 250 mg showed no significant effect on breast cancers in premenopausal women. The aim of this study was to investigate the effects of fulvestrant (F) at a dose of 750mg and compare its effects with tamoxifen (T) in a pre-operative study in premenopausal women. MATERIALS AND METHODS: 60 premenopausal women with operable, invasive estrogen receptor (ER)-positive breast cancer have been randomized to receive either: - 750 mg of F (given as 3 separate intramuscular, 5 ml injections) or - 20 mg of oral T both started 14–16 days before surgery. Breast cancer tissue is being assessed before and after treatment for ER, progesterone receptor (PgR), HER2, and proliferation (Ki67) by immunohistochemistry with FISH for HER 2+. ER and PgR are given as Allred scores and proliferation as % Ki67 positive cells. Results are presented as means (SEM); analysis is by paired t test. RESULTS: ER expression fell significantly with F from a mean Allred score of 7.15 (0.25) to 4.38 (0.61), p < 0.0001. The fall with T from 7.21 (0.19) to 4.14 (0.98) was also significant, p < 0.0001. The fall in ER was significantly greater for F than T, p = 0.02. PgR expression fell significantly with F from a score of 6.11 (0.47) to 4.0 (0.63), p = 0.002. The change with T from 6.34 (0.31) to 5.39 (0.53) was not significant, p = 0.06. The fall in PgR was significantly greater for F than T, p = 0.02. Proliferation F reduced the mean % of Ki 67 positive cells from 14.29 (1.55) to 8.18 (1.55), p < 0.0001, a 48% median reduction. T reduced proliferation from 12.36 (1.71) to 4.12 (0.98), a 71% median reduction, p < 0.0001. Direct comparison of F and T showed no significant difference, p = 0.06. HER2: 5/25 F patients were HER 2+ as were 2/29 T patients. All these 7 patients had a reduction in tumour cell proliferation. Average pain per injection was 1.6/10. Swelling (12%), bruising (16%), and skin sensitivity (12%) were also reported at injection sites with F. Side effects with T included light headedness (10%) and hot flushes (14%). With F hot flushes (16%), loose stools (12%) and headache (28) were reported. All were grade 1 or 2. No patient contacted staff due to adverse events, before routine review. CONCLUSIONS: In premenopausal women 750 mg fulvestrant is well tolerated and significantly reduces ER and PgR expression to a greater degree than tamoxifen. Fulvestrant and tamoxifen both produce reductions in proliferation in ER+ breast cancers. Fulvestrant reduces proliferation in both HER2+ and Her2- tumors. Fulvestrant is biologically active in premenopausal women.