Molecular effects of anastrozole (A) and tamoxifen (T) alone and combined (C) in the IMPACT trial of neoadjuvant treatment of primary breast cancer

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Abstract
537 Background: Aromatase inhibitors and tamoxifen are key agents for endocrine treatment of postmenopausal breast cancer (BrCa). Understanding of their molecular/biological effects in BrCa is needed for their rational application alone or in combination with novel therapeutics. Methods: 330 postmenopausal patients with invasive BrCa (>/=2cm) were randomised to 12wks neoadjuvant therapy with A, T or C in a placebo-controlled double-blind trial (IMPACT). Biopsies were available from a total of 292 patients pre-treatment and at 2 and 12 wks. Immunohistochemical (IC) studies were performed for Ki67, apoptosis (TUNEL), ER, PgR, EGFR (pre) and HER2 (pre). The growth index (GI: Ki67/apoptosis) was calculated. Plasma estradiol (E2) levels were measured. Results: The %age changes in the biomarkers from baseline are shown in the table. IC results for T and C were similar in all respects. The greater reductions in Ki67 in A vs T have been reported. There were greater reductions in GI for A vs T despite the decreases in apoptosis seen with A and profound differences between the treatments in their effect on PgR. After 2wks the reduction in PgR for A, and the increase in PgR for T were correlated with the fall in Ki67 (p=0.003 and 0.027, respectively). After 12wks there was a significantly lower reduction in Ki67 in HER2+ vs HER2- tumours (geo mean: 73% vs 48%) but no significant difference between the treatment groups. Conclusions: Changes in both Ki67 and GI parallel the greater reduction in relapse rate for A vs T and C in the ATAC adjuvant trial. This suggests short-term biomarker changes may predict for long-term outcome in the adjuvant setting but this needs confirmation. The decrease in apoptosis seen with A suggests that estrogen is not an important survival factor in BrCa cells. Early increases in PgR with T are not associated with a poor antiproliferative effect.

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