A VERY LOW DOSE of tamoxifen—5 mg/d, given for 3 years rather than 5 years—halved the risk of breast cancer recurrence or new lesions over placebo in women with breast intraepithelial neoplasia, without producing the usual toxicities seen with the standard dose, Italian researchers reported at the 2018 San Antonio Breast Cancer Symposium.1
Andrea De Censi, MD
“We believe our results have external validity and—given their pragmatic nature and the easy accessibility of tamoxifen—are generalizable,” said Andrea De Censi, MD, of the National Hospital E.O. Ospedali Galliera–Division of Medical Oncology in Genoa, Italy. “Tamoxifen, 5 mg a day (splitting the tablet) or 10 mg every other day, is applicable in clinical practice tomorrow.”
Breast cancer experts at the meeting said this is news they can use. “Looking at these data, I would definitely give lower doses of tamoxifen, especially in patients with atypical ductal hyperplasia and lobular carcinoma in situ,” said Virginia G. Kaklamani, MD, Professor of Medicine at The University of Texas at San Antonio and leader of the Breast Cancer Program at The University of Texas MD Anderson Cancer Center, Houston.
Virginia G. Kaklamani, MD
John Cole, MD
“This information tells me I can perhaps cut back on the dose for patients who are not tolerating tamoxifen. This would help me keep them on the dose, rather than have them abandon therapy,” said John Cole, MD, of the Ochsner Health System in New Orleans.
ALTHOUGH TAMOXIFEN is effective in preventing breast cancer recurrence, its side effects—menopausal symptoms, endometrial cancer, deep-vein thrombosis, and pulmonary embolism— are barriers for its use as a preventive measure. The aim of this de-escalation study was to determine whether a lower dose and shorter duration of tamoxifen therapy would be as efficacious as and better tolerated than the standard dose.
Dr. De Censi and colleagues had previously shown that a dose as low as 1 mg/d is noninferior to 20 mg in decreasing Ki67 (a marker of proliferation), though less effective in modulating serum biomarkers.2 For the current study, the investigators decided 5 mg/d would be a reasonable compromise between activity and safety. He explained that the government- and charity-funded study could not afford to financially support the use of a very large noninferiority trial of tamoxifen at 20 mg/d for 5 years as the control arm.
THE CURRENT phase III multicenter TAM01 trial included 500 women younger than 75 years old (median age = 54 years, 45% premenopausal) with ductal carcinoma in situ (DCIS) that was estrogen receptor–positive (or of unknown status). Approximately 10% of patients enrolled had lobular carcinoma in situ and 20% had atypical ductal hyperplasia. More than 80% had a quadrantectomy, and the rest underwent mastectomy; approximately 57% of DCIS also received radiotherapy.
Patients were randomly assigned after surgery to tamoxifen at 5 mg/d or placebo for 3 years. The primary endpoint was the incidence of invasive breast cancer or DCIS.
After a median follow-up of 5.1 years, 14 of 253 patients (5.5%) in the low-dose tamoxifen arm and 28 of 247 patients (11.3%) in the placebo arm had disease recurrence or new disease in the breast (hazard ratio [HR] = 0.48, 95% confidence interval [CI], 0.26–0.92, P = .024). Contralateral breast cancer developed in 3 (1.2%) and 12 (4.8%) patients, respectively (HR = 0.24, 95% CO, -.007–0.88, P = .018), he reported.
Of the 14 breast events in the tamoxifen arm, 3 were invasive cancers and 11 were DCIS. Of the 28 receiving placebo, 10 were invasive and 18 were DCIS.
THE USE OF low-dose tamoxifen was associated with a median of one additional hot flash per day and no increase in the daily hot flash score (which is figured as frequency multiplied by intensity). Reports of vaginal dryness, pain on intercourse, and musculoskeletal pain/arthralgia were not significantly different.
Treatment adherence (persistent use for at least 2.5 years) was also as high with tamoxifen as with placebo—64.8% and 60.7%, respectively—though, as Dr. De Censi acknowledged, the rates were fairly low overall.
Serious adverse events were observed in 12 patients in the tamoxifen arm and 16 in the placebo arm. In the tamoxifen arm, investigators observed one case of endometrial cancer and one case of venous thromboembolism; one pulmonary embolism was observed among placebo recipients.
Based on findings in the National Surgical Adjuvant Breast and Bowel Project (NSABP)-P-1 prevention trial,3 the expected number of cases of endometrial cancer for patients taking tamoxifen at 20 mg/d would be 2.7, and the expected number of cases of thromboembolism would be 2.4, he added.
“When we compare our low-dose tamoxifen data with results from the NSABP P-1 prevention trial3 and NSABP B-24 DCIS trial4 of tamoxifen at 20 mg/d, we see comparable risk reduction and a significantly reduced risk of serious events,” he said. “The estimated treatment impact at 5 years compares very well with those of other preventive interventions, such as statins for cardiovascular disease.”
The investigators estimated the cumulative incidence of breast events at 5 years as 6.4% with low-dose tamoxifen and 11.0% with placebo and the incidence of serious adverse events as 0.87% and 0.41%, respectively. This translated into a number needed to treat of 22 and a number needed to harm of 218, for a “likelihood of benefit” of 10 (218 divided by 22).
Dr. De Censi said he has been using low-dose tamoxifen for years in patients such as these. He believes that a dose lower than 20 mg/d could potentially be sufficient for stage I cancer as well. But this is an issue that is unlikely to be studied, he told The ASCO Post. “Tamoxifen is too cheap. Who cares about it? There is no commercial interest in developing it further.” ■
DISCLOSURE: Drs. De Censi, Kaklamani, and Cole reported no conflicts of interest.
1. De Censi A, Puntoni M, Guerrieri A, et al: A randomized placebo-controlled phase III trial of low-dose tamoxifen for the prevention of recurrence in women with operated hormone-sensitive breast ductal or lobular carcinoma in situ. 2018 San Antonio Breast Cancer Symposium. Abstract GS3-01. Presented December 6, 2018.
2. Decensi A, Robertson C, Viale G, et al: A randomized trial of low-dose tamoxifen on breast cancer proliferation kand blood estrogenic biomarkers. J Natl Cancer Inst 95:779-790, 2003.
3. Fisher B, Costantino JP, Wickerham DL, et al: Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90:1371-1388, 1998.
4. Allred DC, Anderson SJ, Paik S, et al: Adjuvant tamoxifen reduces subsequent breast cancer in women with estrogen receptor-positive ductal carcinoma in situ: A study based on NSABP protocol B-24. J Clin Oncol 30:1268-1273, 2012.
AT THE SAN ANTONIO Breast Cancer Symposium, several breast cancer experts interviewed by The ASCO Post noted that the approved dose of tamoxifen was arbitrarily set, and the optimal dose is actually unknown. Studies of lower-dose tamoxifen, therefore, are welcomed.
Virginia G. Kaklamani, MD