Long-term Follow-up of the TAM-01 Study, a Phase III Trial of Low-dose Tamoxifen, and Pooled Analysis of Three Studies in Breast DCIS, High-risk Lesions and Microinvasive Disease

The protocol was amended to harmonize endpoint definitions and to specify a pooled analysis combining TAM-01 with other clinical studies evaluating low-dose tamoxifen on BCFI, defined as the time from study entry to the first occurrence of any ipsilateral or contralateral invasive breast cancer (CBC), ipsilateral or contralateral DCIS, regional recurrence, or distant recurrence.

Low-dose tamoxifen (5 mg/day for three years) has emerged as a safer alternative to standard-dose tamoxifen (20 mg/day), effectively reducing the risk of breast cancer recurrence while minimizing adverse events. The TAM-01 phase III trial demonstrated that this regimen decreased subsequent breast cancer events by 42% compared to placebo after 10 years in women with ductal carcinoma in situ (DCIS) or high-risk lesions (atypical ductal hyperplasia, ADH, or lobular carcinoma in situ, LCIS), without exceeding serious adverse events and patient-reported outcomes, thus supporting its wide uptake in the medical community and NCCN guideline inclusion.

The IBIS-I trial reinforced the role of tamoxifen in breast cancer prevention, demonstrating a lasting reduction in breast cancer incidence, particularly in estrogen receptor-positive tumors, with benefits extending beyond the treatment period. Furthermore, real-world evidence indicates strong patient preference for low-dose tamoxifen due to its fewer side effects, which increases adherence in clinical practice. Additionally, studies have shown that low-dose tamoxifen can lower mammographic density, potentially improving screening sensitivity and facilitating earlier cancer detection.

The TAM-01 (EudraCT number: 2007-007740-10) trial was a multicenter, phase III trial comparing 5 mg/day tamoxifen to placebo over 3 years in 500 women aged 75 years or younger with an ECOG performance status of 1 or lower, and hormone-sensitive (ER or progesterone receptor ≥ 1%) or unknown DCIS (69%) or breast intraepithelial neoplasia (ADH, 20% or LCIS, 11%). Women with high-grade or comedo/necrotic DCIS were treated with adjuvant radiotherapy at 50 Gy in 25 fractions. Participants were followed up every 6 months, undergoing annual mammography and transvaginal ultrasound for 3 years of treatment and then being seen annually for 7 years of follow-up. All breast-related events during the trial were centrally adjudicated by an expert committee. The primary endpoint was the incidence of invasive breast cancer and DCIS.

The mean (SD) age at treatment initiation was 54 (9) years, with 58% being postmenopausal women. After a median follow-up of 9.7 years (IQR, 8.3 to 10.9 years), 66 breast cancers were diagnosed (15 in situ; 51 invasive): 25 in the tamoxifen group and 41 in the placebo group (annual rate per 1,000 person-years: 11.3 with tamoxifen vs. 19.5 with placebo; hazard ratio [HR] 0.58; 95% CI, 0.35 to 0.95; p = 0.03). The majority of recurrences were invasive (77%) and ipsilateral (59%). For contralateral breast cancer incidence, there were 6 events in the tamoxifen group and 16 in the placebo group (HR, 0.36; 95% CI, 0.14 to 0.92; p = 0.025). No differences were observed between the groups regarding patient-reported outcomes (menopausal symptoms) or serious adverse events during the extended follow-up period.