Reduction in proliferation with six months of letrozole in women on hormone replacement therapy

Abstract

The objective of this study was to determine if 6 months of the aromatase inhibitor letrozole, administered to postmenopausal women taking a stable dose of hormone replacement remedy, would be safe and would modulate biomarkers of breast cancer risk. The intent was to reduce the proliferation marker Ki-67 while maintaining adequate systemic levels of estradiol so as to avoid perimenopausal symptoms. Postmenopausal women at high risk for development of breast cancer and taking a stable dose of estrogen or estrogen plus progestin were screened by random periareolar fine needle aspiration (RPFNA). To be eligible, the acquired breast epithelial cells had to be characterized as cytologic atypia or borderline atypia with > or =1,000 epithelial cells on the cytomorphology slide; plus > or =500 epithelial cells on a slide processed for Ki-67 immunocytochemistry. Forty-two women were enrolled in the one arm study and received 2.5 mg letrozole per day for 6 months, followed by repeat assessment of biomarkers. Ki-67 was reduced by a median relative value of 66%. There was no significant change in breast cell cytomorphology; ER weighted index score; serum estradiol, testosterone, or IGF-1:IGFBP-3 ratio; mammographic breast density, or frequency or severity of perimenopausal symptoms. Given the dramatic reduction in proliferation, the effect of letrozole on risk and response biomarkers should be explored further in a randomized, placebo-controlled Phase IIB breast cancer chemoprevention trial.

Short-Term Biomarker Modulation Prevention Study of Anastrozole in Women at Increased Risk for Second Primary Breast Cancer

“…In some studies, the cohort consisted of healthy individuals (14), in some, of women on hormonal replacement therapy (HRT; ref. 15) and in some, as in ours and the study by Prowell and colleagues (19), of patients with a history of previous breast cancer of which some had received adjuvant chemotherapy that might have affected baseline biomarkers and changes in these biomarkers. Furthermore, it needs to be acknowledged that many of these studies have a small samples size.…”

“…Fabian and colleagues evaluated the effect of 6 months of letrozole in 42 postmenopausal women taking hormone replacement therapy and, as in our study, no reduction in estradiol levels were seen (15). In contrast, another small study of 32 patients with letrozole did show a reduction in estradiol levels (14).…”

“…Likewise, a similar study using letrozole for 6 months in 42 healthy women did not improve cytologic atypia. However, this particular study did show a significant reduction in Ki-67 in breast FNA samples (15). Finally, in a study of 45 women without breast cancer treated with tamoxifen versus placebo for 1 year, no change in hyperplasia was observed in breast tissue samples obtained by breast core biopsy (20).…”

Identification of Breast Cancer DNA Methylation Markers Optimized for Fine-Needle Aspiration Samples

“…Random periareolar fine-needle aspiration (RP-FNA) samples are frequently used in phase 2 trials of breast cancer prevention for assessments of surrogate endpoint biomarkers (1)(2)(3)(4)(5)(6)(7). DNA methylation is a potentially reversible early event in breast carcinogenesis (8)(9)(10)(11), and is readily assessable in paucicellular RP-FNA samples (12)(13)(14)(15).…”

Relationship Between Breast Density and Selective Estrogen-Receptor Modulators, Aromatase Inhibitors, Physical Activity, and Diet

“…49 Changes in BD with AIs (letrozole, 2.5 mg/d; anastrozole, 1 mg/d; exemestane, 25 mg/d) were assessed in 10 studies. [13][14][15][16][17][53][54][55][56] Four of the studies used letrozole alone; there was 1 study each on anastrozole and exemestane, and others combined 2 of the 3 AIs. Of these, 4 were prospective arm trials and 3 were RCTs.…”