Abstract GS3-01: A randomized placebo controlled phase III trial of low dose tamoxifen for the prevention of recurrence in women with operated hormone sensitive breast ductal or lobular carcinoma in situ
Authors: DeCensi A , Puntoni M , Guerrieri Gonzaga A , Avino F , Cortesi L , Donadio M , Pacquola M , Falcini F , Gulisano M , Digennaro M , Tienghi A , Cagossi K , Pinotti G , Varicchio C , Caviglia S , Boni L , Bonanni B 
Published: May 2019

Abstract
Background: Tamoxifen is an effective drug for breast cancer prevention and treatment, but the risk of endometrial cancer and venous thromboembolism has limited its broader use. We have repeatedly shown in biomarker trials that the minimal effective dose of tamoxifen is lower than 20 mg/day, but a definitive answer on efficacy and safety required a phase III trial. The optimal treatment of ductal carcinoma in situ (DCIS) is still controversial.
Methods: We conducted a phase III trial of tamoxifen (T), 5 mg/day versus placebo (P) in women with operated hormone sensitive breast intraepithelial neoplasia (DCIS or LCIS). Women with G3, positive margins or comedo/necrosis DCIS received radiotherapy. Women were seen every 6 months with an annual mammography for at last 5 years after randomization. Initial statistical calculations were revised according to the lower than expected accrual, and the Independent Data Safety Monitoring Board recommended the disclosure of results as 80% of the originally expected events were observed.
Results: Between November 1, 2008 and March 31, 2015 a total of 500 women were randomized to either T, 5 mg/day or P for 3 years. A total of 10 patients are not assessable becuse of consent withdrawal or drop out. The main subject characteristics were well balanced between arms. As of May 31, 2018, after a median follow-up of 5.1 years (interquartile range, 3.9-6.3), there were 14 recurrences in the T arm and 29 in the P arm (hazard ratio=0.48, 95% CI, 0.25-0.89, p=0.02). The incidence rate of events was 11.8/1000 py in the T arm and 24.9/1000 py in the P arm. Most recurrences were invasive breast cancers: 11/14 (78%) in the T arm and 16/29 (55%) in the P arm. There were 8 serious adverse events in the T arm and 12 in the P arm, including 2 arterial events in each arm, 2 superficial phlebitis in the T arm and 1 endometrial cancer (annual rate 0.85/1000 py) in the T arm. There were 6 versus 4 second primary cancers in the T and P arm, respectively, and 2 deaths in the P arm. Menopausal symptoms were more frequent in the T arm and will be reported in details at the conference.
Baseline characteristics Tamoxifen (n=246)Placebo (n=244) mean (SD)mean (SD)Age (yrs) 54.0 (9.4)53.7 (9.1)Body Mass Index (kg/m2) 25.7 (4.8)25.3 (4.2) n (%)n (%)Menopausal statusPre-110 (45)107 (44) Post-136 (55)137 (56)Type of lesionDCIS221 (89)220 (90) LCIS25 (10)24 (10)Type of surgeryConservative (Q/L)206 (84)200 (82) Mastectomy39 (16)44 (18) Axillary dissection1 (0)-SD=standard deviation; DCIS=ductal carcinoma in situ; LCIS=lobular carcinoma in situ; Q=quadrantectomy; L=lumpectomy
Conclusions: Tamoxifen at the dose of 5 mg/day can halve the incidence of recurrence in women with operated hormone sensitive DCIS or LCIS with a limited toxicity, providing a valid treatment option in women with disease. In addition, this study has important implications for the preventive therapy of high risk unaffected women.
ClinicalTrials.gov Identifier: NCT01357772; Supported by the Italian Ministry of Health - RFPS-2006-1-339898 and the Italian Association for Cancer Research (AIRC) - IG 2008 Grant no. 5611.
Citation Format: DeCensi A, Puntoni M, Guerrieri Gonzaga A, Avino F, Cortesi L, Donadio M, Pacquola M, Falcini F, Gulisano M, Digennaro M, Tienghi A, Cagossi K, Pinotti G, Varicchio C, Caviglia S, Boni L, Bonanni B. A randomized placebo controlled phase III trial of low dose tamoxifen for the prevention of recurrence in women with operated hormone sensitive breast ductal or lobular carcinoma in situ [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS3-01.