The TAM01 trial looked at whether a 5-mg/day dose of tamoxifen was effective in patients with breast intraepithelial neoplasia, or if the 20-mg/day dose was still the best option.
For patients with intraepithelial neoplasia, treatment with tamoxifen at a dose of only 5 mg/day for 3 years, rather than the standard 20 mg/day, can reduce recurrence at a similar rate to the higher dose, according to the results of the TAM01 study. The regimen did not significantly worsen menopausal symptoms or major adverse events compared with placebo.
Intraepithelial neoplasia represents 15% to 25% of all breast cancers, and includes a heterogeneous spectrum of disorders including atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS), and lobular carcinoma in situ (LCIS). “We know very well that tamoxifen is very effective in prevention,” but its potential side effects, including endometrial cancer, deep vein thrombosis (DVT), and menopausal symptoms, act as a barrier to its use, said Andrea DeCensi, MD, of the Ospedali Galliera in Genoa, Italy. He presented these results (abstract GS3-01) at the San Antonio Breast Cancer Symposium (SABCS), held December 4–8.
The study included 500 women aged less than 75 years with intraepithelial neoplasia. They were randomized to receive either tamoxifen 5 mg/day for 3 years, or to placebo; the median follow-up in the study was 5.1 years. Patients had a mean age of 54 years, and just under half in both groups were premenopausal. Most of the cohort had DCIS (69% of tamoxifen patients, 70% of placebo patients), followed by ADH (20% in both groups), and LCIS (11% and 10%, respectively).
In total, there were 42 breast cancer or DCIS events. There were 28 such events in the placebo group compared with 14 in the tamoxifen group, for a hazard ratio (HR) of 0.48 (95% CI, 0.26–0.92; P = .024). The placebo patients had a rate of 23.9 events per 1,000 person-years, compared with 11.6 events per 1,000 person-years with tamoxifen.
There were 12 cases of contralateral breast cancer in the placebo group, compared with 3 cases in the tamoxifen group, for an HR of 0.24 (95% CI, 0.07–0.87; P = .018).
There was one case of endometrial cancer in the tamoxifen group, and none in the placebo patients; there were four other neoplasms with tamoxifen and six with placebo. Both groups had one case of DVT or pulmonary embolism, and both had two cases of coronary heart disease. DeCensi said that with 20 mg/day of tamoxifen, 2.7 cases of endometrial cancer and 2.4 cases of DVT/pulmonary embolism would be expected.
Notably, the regimen did not appear to significantly worsen menopausal symptoms. There was a significant increase in the frequency of daily hot flashes (P = .05), but the absolute increase was less than one. There was no difference between tamoxifen and placebo with regard to vaginal dryness or pain during intercourse (P = .57), or with regard to musculoskeletal pain/arthralgia (P = .84).
“We think our results have external validity due to the pragmatic nature of the trial,” DeCensi said. He noted that the currently available 10-mg pill could be taken every other day to achieve the 5-mg/day regimen, “which I think is applicable in clinical practice tomorrow.”
Virginia Kaklamani, MD, of UT Health San Antonio and co-chair of SABCS, who was not involved with the study, noted that drug trials often focus on the maximum tolerated dose rather than the dose that is actually needed to produce the desired effect. “This is an example of a drug that’s been out for 50 years, and we’ve thought before that we don’t need that full dose,” she said. “A drug doesn’t work if you don’t take it, so if you can find ways to take the drug, like at these lower doses, these women are going to benefit.” She noted that with the current results, she would give ADH and LCIS patients the lower dose, though she would like to see further follow-up before changing practice for DCIS patients. Even in those patients, though, if a patient is struggling with toxicity at 20 mg/day, “I’d be extremely happy giving this lower dose.”