Use of low-dose tamoxifen conferred a sustained reduction in risk for recurrence among women with noninvasive breast cancer, according to updated results from the randomized, phase 3 TAM-01 trial.

The findings — presented at San Antonio Breast Cancer Symposium — also showed a low risk for death at 10-year follow-up.

“Four years ago, we presented 5-year data on low-dose tamoxifen, which showed a significant reduction in risk for recurrence,” Andrea DeCensi, MD, director of the medical oncology unit at National Hospital E.O. Ospedali Galliera — S.C. Oncologia Medica in Italy, said during a presentation.

After SABCS in 2018, ASCO and the U.S. Preventive Services Task Force guidelines included low-dose tamoxifen for preventive therapy in high-risk lesions. In addition, National Comprehensive Cancer Network recommended low-dose tamoxifen after ductal carcinoma in situ for symptomatic patients or those who were unwilling or unable to take full-dose tamoxifen, DeCensi said.

“Most importantly, [low-dose tamoxifen] became the most popular treatment [for] patients with high-risk lesions across several prominent U.S. centers, with lower discontinuation rates vs. 20 mg daily tamoxifen, raloxifene or aromatase inhibitors,” DeCensi said.

Background and methods

As Healio previously reported, the TAM-01 trial included 500 women (mean age, 54 years) undergoing treatment for DCIS, lobular carcinoma in situ (LCIS) or atypical ductal hyperplasia (ADH) across 14 centers in Italy.

Researchers assigned patients to either 5 mg daily tamoxifen (n = 253) or placebo (n = 247). Treatment continued for 3 years, with a minimum 2 years of additional follow-up. Incidence of invasive breast cancer or DCIS served as the primary endpoint.

Results of 5-year follow-up data presented at SABCS in 2018 showed a 52% decrease in cumulative risk for breast intraepithelial neoplasia recurrence with low-dose tamoxifen.

Researchers observed 14 primary events in the low-dose tamoxifen group vs. 28 events in the placebo group (HR = 0.48; 95% CI, 0.26-0.92). They also reported a significant decline in contralateral breast cancer cases in the low-dose tamoxifen group (12 vs. 3; HR = 0.24; 95% CI, 0.07-0.87). Results showed no significant differences in daily hot flashes, vaginal dryness/pain at intercourse, or musculoskeletal pain/arthralgia.

At SABCS, DeCensi presented updated data on breast cancer recurrence based on median follow-up of 9.7 years (range, 8.3-10.9).

Results

Researchers observed a 42% reduced risk for recurrence with low-dose tamoxifen.

Subgroup analyses showed reductions in ipsilateral breast events (16 vs. 23; HR = 0.68; 95% CI, 0.36-1.28) and contralateral breast events (6 vs. 16; HR = 0.36; 95% CI, 0.14-0.92) in the low-dose tamoxifen group.

“The effect on contralateral breast events reopens the door for prevention in high-risk unaffected women,” DeCensi said.

Researchers additionally reported a benefit with low-dose tamoxifen among post-menopausal women (HR = 0.43; 95% CI, 0.2-0.91), those with a BMI greater than 30 kg/m² (HR = 0.26; 95% CI, 0.07-0.97), those who underwent mastectomy (HR = 0.2; 95% CI, 0.4-0.97) and those with DCIS (HR = 0.49; 95% CI, 0.27-0.89).

“In the DCIS cohort, we observed a remarkable 50% reduction in recurrence risk with 3-year low-dose tamoxifen, which — to us — provides a new standard of care for this cohort,” DeCensi said.

The safety of low-dose tamoxifen appeared consistent with previously reported findings, researchers noted.

Study limitations included the limited power for interactions and subgroup analysis, as well as the lack of vis-à-vis comparison with 20 mg daily tamoxifen. However, a noninferiority trial would be poorly accepted among patients with high-risk lesions due to toxicity of the 20-mg dose, DeCensi said.

“The lack of the 5 mg dose on the market is a reflection of zero commercial interest for this drug,” he added. “However, the 10-mg dose administered on alternate days is a reasonable alternative due to its long half-life.”

Implications

The findings are one more example of a missed optimal dose for a targeted agent, DeCensi said.

“Our aim is to attain a safe and equitable treatment that could cost $2 to $3 per month vs. the cost of other modern treatments, which is merciless and embarrassing,” he said. “My pledge to young investigators is to not miss the unique beauty of clinical academic research.”