Background: Tamoxifen, a key chemopreventive and adjuvant endocrine therapy (ET) for breast cancer, is suggested to alter breast cancer risk factors including circulating hormones (estrogen and insulin-like growth factors (IGFs)) and breast density. However, the biological underpinnings of tamoxifen’s effect on these factors remain unclear. This dissertation evaluated effects of tamoxifen on estrogen metabolites (EMs), explored associations between circulating IGFs (IGF-I and IGFBP-3) and volume average sound speed measures (VASS) of breast density, and synthesized evidence from real-world studies to meta-analyze adjuvant ET in relation to contralateral breast cancer (CBC) risk.

Methods: Within the Ultrasound Study of Tamoxifen, serial serum samples collected prior to and 12 months after tamoxifen treatment were used to assess longitudinal changes (paired t-tests) in 15 circulating EMs among postmenopausal women (n=23) (Aim 1), and changes in IGFs and VASS (n=53) (Aim 2). Multivariable linear regression examined associations between metabolites of tamoxifen and estrogen among pre- (n=33) and postmenopausal women (n=27) (Aim 1) and concomitant changes in IGFs and VASS (n=53) (Aim 2), 12 months after treatment initiation. In Aim 3, a random effects meta-analysis of observational studies (n=17, 287,576 participants) estimated relative risks (RR) and 95% confidence intervals (CI) for associations between ET and CBC risk among primary breast cancer patients overall, by menopausal status and CBC estrogen receptor (ER)-subtype.

Results: Circulating 2-OH and 16-OH pathway EMs, IGF-I, and IGF-I:IGFBP-3 decreased 12 months after tamoxifen initiation (p <0.05; Aims 1 and 2). No associations were observed between concomitant changes in IGFs and VASS among tamoxifen-treated patients (Aim 2). In meta-analyses (Aim 3), endocrine therapy was associated with reduced CBC risk (RR: 0.62, 95% CI: 0.53, 0.73), with a greater reduction observed among premenopausal (RR: 0.58, 95% CI: 0.43, 0.78) versus postmenopausal women (RR: 0.72, 95% CI: 0.60, 0.87). Endocrine therapy reduced the risk of ER-positive (RR: 0.55, 95% CI: 0.43, 0.70) but not ER-negative CBC.

Conclusion: The tamoxifen mediated decline of circulating 2-OH, 16-OH and IGF-I provides etiologic insight into the biomechanisms of tamoxifen on breast carcinogenesis. Meta-analyses of observational studies further support a chemopreventive role of endocrine therapy on CBC risk, particularly, ER-positive CBC.