The use of low-dose tamoxifen was shown to significantly reduce the risk of new and recurrent disease following surgery in women diagnosed with breast intraepithelial neoplasia but it did not cause more serious adverse events compared with placebo.
Andrea De Censi, MD
The use of low-dose tamoxifen was shown to significantly reduce the risk of new and recurrent disease following surgery in women diagnosed with breast intraepithelial neoplasia (IEN) but it did not cause more serious adverse events compared with placebo, according to data from the phase III TAM-01 trial presented at the 41st Annual San Antonio Breast Cancer Symposium (SABCS).1
“We know tamoxifen is effective in prevention, but its toxicity…represents an important barrier for its use in a population at increased risk for breast cancer.” said Andrea De Censi, MD, director of the medical oncology unit at the National Hospital E.O. Ospedali Galliera—SC Oncologia Medica in Genoa, Italy, who presented the findings at the meeting.
The current standard for tamoxifen therapy following surgical removal for this patient population is 20 mg daily for 5 years. However, patient compliance is often an issue due to its toxicity profile.
“It is not clear what is the minimal active dose to illicit its biological and clinical effect,” De Censi said. Study investigators hypothesized that a lower dose of tamoxifen over a shorter duration could be equally as effective yet less toxic than the current stand dose.
At the median follow-up of 5.1 years, there were 14 (5.5%) events of disease recurrence in the tamoxifen arm versus 28 (11.3%) with the placebo (HR 0.48; 95% CI, 0.26-0.92; P = .024). The annual risk of events was calculated to be 11.6 versus 23.9 per 1000 patients, representing a 52% reduction in the cumulative risk of disease.
The risk of contralateral breast cancer with low-dose tamoxifen was reduced by 75% when compared with placebo (HR 0.24; 95% CI, 0.07-0.87; P = .018), suggesting a strong preventative potential. However, De Censi said that more data is needed because this is based on just 15 events.
There was no significant difference in patient characteristics between the tamoxifen and placebo arms with most patients having DCIS (69% vs 70%), followed by ADH (20% vs 20%) and LCIS (11% vs 10%), respectively. Median patient age was 54 years and less than half (46% vs 44%) were premenopausal.
There was 1 case each of deep vein thrombosis (DVT) or pulmonary embolism (PE) and 2 events of coronary heart disease in both arms. There was 1 case of endometrial cancer with tamoxifen; other neoplasms occurred in 4 patients taking tamoxifen versus 6 in the placebo group. Deaths occurred in 1 patient taking tamoxifen versus 2 with placebo.
Comparing this with historical data from a trial in which women received the standard dose of tamoxifen at 20 mg daily,2 De Censi said the expected risk of endometrial cancer for this group would be 2.7 events and the risk for DVT or PE would be 2.4 events with the higher dose of the drug.
“In this de-escalation trial, toxicity is as important as efficacy,” De Censi said.
Frequency and intensity of hot flashes, the most frequent adverse event associated with tamoxifen, was assessed using self-reported questionnaire data. “There is a slight, borderline significant increase in the number of hot flashes per day—less than 1 hot flash extra on tamoxifen; [but] if we multiply the frequency by the intensity, there was no significant difference between the 2 arms,” he said.
De Censi went on to emphasize that there was no significant difference in the incidence of vaginal dryness/pain during intercourse and musculoskeletal pain/arthralgia between the 2 groups.
Virginia Kaklamani, MD, leader of the Breast Cancer Program at UT Health San Antonio and SABCS codirector, highlighted the importance of these findings. “When you look at drug development, in many cases…we pay attention to the [maximum tolerated dose, and] we end up using them at higher doses than we need to.”
She added that patient compliance is an important part of tamoxifen’s ability to control disease and these kinds of trials on standard-of-care therapies highlight ways that clinicians can continue to improve patients’ quality of life and survival. Even with the reduced dosage, patient adherence in this trial left room for improvement. De Censi noted adherence was 64.8% versus 60.7% for the tamoxifen versus placebo arms, respectively.
“Looking at these data, especially looking at the ADH and the LCIS, I would give lower doses of tamoxifen…and if I had a [patient with DCIS] who is not tolerating tamoxifen at the 20 mg dose, I would be happy to lower it to 5 mg based in this data,” she said.
Based on the lack of availability of a 5 mg tamoxifen dose in some markets, De Censi concluded that 10 mg may be administered to patients every other day.
Women aged <75 years with atypical ductal carcinoma (ADH), lobular carcinoma in situ (LCIS), and ER-positive or ductal carcinoma in situ (DCIS) of unknown origin were included in the study. Patients were randomized 1:1 to receive either tamoxifen (n = 253) at 5 mg daily or placebo (n = 247) for 3 years with at least 2 years of follow-up. The primary endpoint was the incidence of invasive breast cancer or DCIS.