Abstract PD3-08: Effects of low dose tamoxifen on circulating risk biomarkers in a phase III trial in breast pre-invasive disease
Authors: Johansson Harriet , Puntoni Matteo , Macis Debora , Aristarco Valentina , Guerrieri-Gonzaga Aliana , Serrano Davide , Caviglia Silvia , Cortesi Laura , Taverniti Cristiana , Ponti Antonio , Pacquola Maria Grazia , Gulisano Marcella , Falcini Fabio , Digennaro Maria , Carriello Anna , Cagossi Katia , Pinotti Graziella , Webber Tania Buttiron , Lazzeroni Matteo , Bonanni Bernardo , Boni Luca , DeCensi Andrea 
Published: March 2020

Abstract
Background: We recently showed that low dose (5mg/d) tamoxifen (babytam) for 3 years can halve the incidence of new breast neoplastic events in hormone sensitive or unknown breast pre-invasive neoplasia after surgery with limited toxicity (DeCensi et al JCO 2019; 37:1629-37). Here we report the results of circulating surrogate endpoint biomarkers of breast cancer risk with special attention to the risk of ovarian stimulation observed with the full dose in premenopausal women. Methods: Five hundred women 75 years old or younger were randomized to babytam or placebo (PLA). A subgroup of 406 women consented for collection of morning fasting serum at baseline (0), 1 (1Y) and 3 years (3Y) of treatment. There was a loss of about 25% of blood sampling at 3Y. Serum IGF-I, IGFBP-3, SHBG and C-reactive Protein (CRP) were performed on all available samples. Estradiol and testosterone were determined in a subsample (n=285) to determine the extent of ovarian stimulation by babytam in premenopausal women. We used Mann-Whitney test for univariate comparisons and linear regression modeling for multivariate analyses setting changes from baseline (1Y or 3Y minus baseline values) as dependent variable and treatment arm, age, BMI and baseline biomarkers values as explanatory factors. We tested treatment*menopausal status as interaction term. COX P-H model was used to calculate hazard ratio for CRP increase. Results: At baseline, all biomarkers were evenly balanced between arms (data not shown). IGF-I decreased significantly on babytam as compared to PLA. The difference of the changes between arms was -20 ng/mL after 1Y (p&lt;0.001) and -23 after 3Y (p&lt;0.001). A treatment by menopausal status interaction was observed after 1Y (p=0.017) and 3Y (p=0.058), with a steeper decrease in postmenopausal (-25, p&lt;0.001 both after 1Y and 3Y) as compared to premenopausal women (-15, p=0.007 after 1Y and -17, p=0.009 after 3Y). IGFBP-3 increased significantly on babytam, without effect modification by menopausal status. The difference between arms was +0.26 ug/mL after 1Y (p=0.006) and +0.19 after 3Y (p=0.024). SHBG increased markedly on babytam, irrespective of menopausal status. The difference between arms from 0 to 1Y and 3Y was 24 nMol/L (p&lt;0.001). CRP levels followed a trend towards a decrease with babytam (-0.172 mg/dL, p=0.057 after 1Y and -0.091, p=0.108 after 3Y), without effect modification by menopausal status. There was no significant increase in serum estradiol after 1Y with babytam overall (+12 pg/mL, p=0.106), but a trend to an interaction with menopausal status (p=0.079): +17 (p=0.361) in premenopausal women versus +3 (p=0.284) in postmenopausal women. Similarly, there was no overall effect of babytam on testosterone after 1Y (-0.008 ng/mL, p=0.518), but a significant effect modification by menopausal status (p=0.001), showing an increase of +0.056 (p=0.006) in premenopausal women, and a decrease of -0.045 (p=0.006) in postmenopausal women. Irrespective of treatment, the increase in CRP at 3Y was significantly higher in women who experienced recurrence compared to women who did not (Mann-Whitney p=0.009). An increase in CRP was associated with a HR of 2.9 (95% CI, 1.0-8.3, p=0.05) as compared to women with a decreased or stable CRP levels. Conclusions: Babytam for 3 years exhibits a favorable effect on sex hormones and IGFs with only a slight increase of estradiol in premenopausal women which is far below that observed with 20 mg and is well compensated by a significant increase in SHBG. These findings further support the use of babytam as an effective and safe treatment for high risk individuals. ClinicalTrials.gov Identifier: NCT01357772. Supported by the Italian Ministry of Health (RFPS-2006-339898), the Italian Association for Cancer Research (IG 2008 Grant No 5611) and the Italian League against Cancer (LILT 7-08).
Citation Format: Harriet Johansson, Matteo Puntoni, Debora Macis, Valentina Aristarco, Aliana Guerrieri-Gonzaga, Davide Serrano, Silvia Caviglia, Laura Cortesi, Cristiana Taverniti, Antonio Ponti, Maria Grazia Pacquola, Marcella Gulisano, Fabio Falcini, Maria Digennaro, Anna Carriello, Katia Cagossi, Graziella Pinotti, Tania Buttiron Webber, Matteo Lazzeroni, Bernardo Bonanni, Luca Boni, Andrea DeCensi. Effects of low dose tamoxifen on circulating risk biomarkers in a phase III trial in breast pre-invasive disease [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD3-08.