Randomized Placebo Controlled Trial of Low-Dose Tamoxifen to Prevent Recurrence in Breast Noninvasive Neoplasia: A 10-Year Follow-Up of TAM-01 Study

Abstract

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. PURPOSE Five-year data of the phase III trial TAM-01 showed that low-dose tamoxifen at 5 mg once daily administered for 3 years in women with intraepithelial neoplasia (IEN) reduced by 52% the recurrence of invasive breast cancer or ductal carcinoma in situ (DCIS), without additional adverse events over placebo. Here, we present the 10-year results. METHODS We randomly assigned 500 women with breast IEN (atypical ductal hyperplasia, lobular carcinoma in situ [LCIS], or hormone-sensitive or unknown DCIS) to low-dose tamoxifen or placebo after surgery with or without irradiation. The primary end point was the incidence of invasive breast cancer or DCIS. RESULTS The TAM-01 population included 500 women (20% atypical ductal hyperplasia, 11% LCIS, and 69% DCIS). The mean (±SD) age at the start of treatment was 54 ± 9 years, and 58% of participants were postmenopausal. After a median follow-up of 9.7 years (IQR, 8.3-10.9 years), 66 breast cancers (15 in situ; 51 invasive) were diagnosed: 25 in the tamoxifen group and 41 in the placebo group (annual rate per 1,000 person-years, 11.3 with tamoxifen v 19.5 with placebo; hazard ratio [HR], 0.58; 95% CI, 0.35 to 0.95; log-rank P = .03). Most recurrences were invasive (77%) and ipsilateral (59%). Regarding contralateral breast cancer incidence, there were six events in the tamoxifen arm and 16 in the placebo arm (HR, 0.36; 95% CI, 0.14 to 0.92; P = .025). The number needed to be treated to prevent one case of breast event with tamoxifen therapy was 22 in 5 years and 14 in 10 years. The benefit was seen across all patient subgroups. There was a significant 50% reduction of recurrence with tamoxifen in the DCIS cohort, which represents 70% of the overall population (HR, 0.50; 95% CI, 0.28 to 0.91; P = .02). No between-group difference in the incidence of serious adverse events was reported during the prolonged follow-up period. CONCLUSION Tamoxifen 5 mg once daily for 3 years significantly prevents recurrence from noninvasive breast cancer after 7 years from treatment cessation without long-term adverse events.

Endocrine Therapy for Primary and Secondary Prevention After Diagnosis of High-Risk Breast Lesions or Preinvasive Breast Cancer

“…The reduction of breast cancer diagnoses with low-dose tamoxifen presented in the TAM-01 study was significant with a HR of 0.50 (95% CI, 0.28 to 0.91; P = .02) among the subset of patients with DCIS. 8 However, this benefit was not separated by location (ipsilateral or contralateral breast) for patients with DCIS in the current or previous reports of the study. And among patients who received RT (45% of cohort, and assuming radiation was restricted to DCIS, 62% of the patients with DCIS), the benefit of low-dose tamoxifen on breast diagnoses did not meet significance (HR, 0.67; 95% CI, 0.32 to 1.39).…”

“…In the trial's initial publication, at 5-year median follow-up, tamoxifen 5 mg once daily was associated with 52% reduction in invasive or noninvasive breast cancer. 9 In the companion to this article, Lazzeroni et al 8 report a durable 42% risk reduction at nearly 10 years of median follow-up. Unlike with tamoxifen 20 mg once daily, there does not appear to be an increased risk of endometrial cancer or VTE with 5 mg once daily, although the sample size may be too small to capture these rare events.…”

“…Women on tamoxifen 5 mg once daily reported significantly more hot flashes, although the absolute difference from placebo was small (mean 2.1/d v 1.5/d), with no differences in hot flash intensity or vaginal or musculoskeletal symptoms. 8…”

Tamoxifen Dose De-Escalation: An Effective Strategy for Reducing Adverse Effects?

“…One study was performed in healthy women receiving HRT ( n = 1884) and the other study was performed in patients with carcinoma in situ ( n = 500). No significant difference was found (0.5% for tamoxifen vs. 0.2% for placebo [RR 2.64, 95% CI 0.51–13.6] and 0.4% for both tamoxifen and placebo, with a p -value of 1.0, respectively) over a follow-up period of 6–10 years [ 45 , 67 ]. Although the first mentioned study was in women receiving HRT [ 45 ], which might have influenced the VTE incidence because HRT leads to a higher VTE risk itself [ 68 ], the absolute incidence for VTE is very low.…”

Expanding Endocrine Therapy Options for Patients With Ductal Carcinoma In Situ—More Work to Do

“…Local chemoprevention that minimizes systemic disruption may be well suited to this population, where intensive surveillance can impact patient quality of life and choice for risk-reducing surgery. Low-dose tamoxifen is effective among women with high-risk lesions and may be a better comparator to topical tamoxifen. The continued discovery of novel alternatives to standard treatment is critical—topical tamoxifen holds promise in expanding patient-centered endocrine therapy options for women with DCIS.…”