Low-dose adjuvant tamoxifen (babytam) lowers recurrence from non-invasive breast cancer at 10 years in women with breast intraepithelial neoplasia

Low-dose tamoxifen, also known as babytam, has previously demonstrated its efficacy as adjuvant treatment for women with breast intraepithelial neoplasia (IEN), based on the results of the TAM-01 trial. At SABCS 2022, the 10-year follow-up outcomes of this trial were presented, showing that babytam, administered for three years, lowers recurrence from non-invasive breast cancer at 10 years without increasing the incidence of adverse events, demonstrating a carryover effect.

Previously, the TAM-01 trial demonstrated the efficacy of low-dose tamoxifen (5mg/day, known as babytam) as adjuvant treatment for women with breast intraepithelial neoplasia (IEN). The 5-year results of this trial were presented at SABCS 2018. At this time, the administration of babytam resulted in a 52% reduction of recurrence (invasive breast cancer (BC) or DCIS) (HR[95%CI]: 0.48[0.26-0.92]), and a 76% reduction in collateral BC (HR[95%CI]: 0.24[0.07-0.87]) vs. placebo. There were no differences in serious adverse events (AEs) or patient-reported outcomes (PROs), except for less than an extra hot flash per day on babytam, between the arms. After SABCS 2018, ASCO and USPSTF guidelines included babytam for preventive therapy of patients with high-risk lesions (HRL), while NCCN guidelines recommended babytam after DCIS if the patient is symptomatic or unwilling/unable to take a full dose. More importantly, babytam became the most popular treatment in HRL in the US, with a lower discontinuation rate vs. 20 mg/day of raloxifene or aromatase inhibitors (AIs). The 10-year follow-up results of TAM-01 were presented at SABCS 2022.

Study design

The phase III TAM-01 trial enrolled women <75 years old with HRL breast IEN, including atypical ductal hyperplasia (ADH), lobular carcinoma in situ (LCIS), ER+ or unknown ductal carcinoma in situ (DCIS). In total, 500 patients were randomised 1:1 to tamoxifen 5mg/day (babytam) or placebo, and at least seven-years of follow-up. The primary endpoint was the incidence of invasive BC or DCIS. Visits and quality of life (QoL) questionnaires were carried out every six months for three years. Thereafter, annual mammography and clinical visits were performed.

Results

After a median follow-up of 9.7 years, there was still a significant 42% reduction of breast cancer or DCIS with babytam, which continues up to 10 years or more, demonstrating a carryover effect (HR[95%CI]: 0.58[0.35-0.95], p= 0.028). In the subgroup analyses, there was a non-significant 32% reduction of ipsilateral breast events with babytam (HR: 0.68[0.36-1.28], p= 0.227) and a significant 64% reduction of contralateral breast cancer events (HR[95%CI]: 0.36[0.14-0.92], p= 0.025).  The benefit was evident across subgroups except for current smokers, although the trial was not powered to detect interactions. Interestingly, there was a significant reduction in recurrence in postmenopausal women, obese women, women undergoing mastectomy, and in the DCIS cohort.  In the DCIS cohort, there was a remarkable 50% reduction of recurrences with babytam (HR[95%CI]: 0.50[0.28-0.91], p= 0.02) for 3 years, which suggests babytam as a new standard-of-care for this cohort.  There were 66 primary breast events. Tumour characteristics of the 66 events were not different between babytam and placebo. Most recurrences were invasive, ipsilar and T1 stages. Ten-year data confirm the safety of this approach. Only one case of endometrial cancer was observed vs. five predicted if administering 20 mg/day (based on the NSABP-P1 study data). No differences between arms were observed in deep vein thrombosis, pulmonary embolisms, neoplasms or other serious AEs. Interestingly, cataracts and endometrial polyps, which are two non-serious but frequent AEs, were not significantly increased with babytam. There were no differences in the amount of deaths from BC or other causes between the arms.

Conclusions

After 10 years of follow-up, the results of TAM-01 demonstrate that babytam 5 mg/day, administered for three years, lowers recurrence from noninvasive breast cancer at 10 years without significantly increasing the incidence of AEs, demonstrating a carryover effect. This benefit was observed across all subgroups, though with limited power. In women with DCIS, the reduction in recurrences suggests babytam as a new potential standard-of-care for this cohort. Furthermore, the low risk of death supports treatment de-escalation in DCIS.

Reference

De Censi A, Lazzeroni M, Puntoni M, et al. 10-year results of a phase 3 trial of low-dose tamoxifen in non-invasive breast cancer. Presented at SABCS 2022; Abstract GS4-08.