Nonsignificant Reduction in Breast Cancer Risk Seen With Low-Dose Tamoxifen in Postmenopausal Hormone Replacement Therapy Users


Key Points

  • Phase III study results showed that low-dose tamoxifen yielded a nonsignificant 20% reduction in the risk of breast cancer in postmenopausal women receiving hormone replacement therapy.
  • Favorable trends with tamoxifen treatment were noted in certain subgroups, including those with luminal A tumors and users of hormone replacement therapy for less than 5 years.
  • Vasomotor symptoms were 50% more common in the tamoxifen group than in the placebo group.

In postmenopausal women receiving hormone replacement therapy, low-dose tamoxifen did not significantly reduce the risk of breast cancer but did increase climacteric symptoms, according to the phase III study results presented by DeCensi et al in the Annals of Oncology. However, beneficial trends in some subgroups were noted by the investigators, suggesting that the treatment may warrant further study.

Study Details

To determine the efficacy of low-dose tamoxifen in decreasing the risk of breast cancer in recently menopausal women receiving hormone replacement therapy, the investigators performed this phase III, double-blind, placebo-controlled prevention trial. A total of 1,884 women were randomly assigned to receive either tamoxifen (5 mg/d) or placebo for 5 years.

Eligibility criteria included current hormone replacement therapy use or de novo hormone replacement therapy and a normal mammogram within 6 months. More than 55% of study patients had received hormone therapy replacement for less than 5 years, and approximately 40% of both groups were at least 55 years of age.

Every 6 months, clinical examinations were repeated, and mammography was done every year. At baseline, transvaginal ultrasonography was performed; it was repeated in the case of atypical bleeding. After the 5 study years, clinical visits and mammography were performed annually up to 10 years.

Histologic type and grade were determined by central pathology assessment. The tumors were classified immunohistochemically into four molecular subtypes: (1) luminal A, estrogen receptor–positive or progesterone receptor–positive, and Ki-67 < 14%; (2) luminal B, estrogen receptor–positive or progesterone receptor–positive, and either Ki-67 ≥ 14% with HER2-negative or HER2-positive regardless of the Ki-67 level; (3) HER2-positive, estrogen receptor–negative, and progesterone receptor–negative; and (4) triple-negative, with all receptors negative.

Favorable Trends Seen in Certain Subgroups

A nonsignificant 20% reduction in the risk of breast cancer was demonstrated with low-dose tamoxifen. In addition, a 50% borderline significant reduction was seen in women who received treatment for more than 1 year, according to a sensitivity analysis adjusted for nonadherence. A total of 24 breast cancers were seen in the placebo group, compared with 19 in the tamoxifen group (risk ratio [RR] = 0.80; 95% confidence interval [CI] = 0.44?1.46), after a mean ± standard deviation follow-up of 6.2 ± 1.9 years.

However, favorable trends with tamoxifen were noted in certain subgroups. They included women with luminal A tumors (RR = 0.32; 95% CI = 0.12–0.86), those with progesterone receptor–positive tumors (RR = 0.43; 95% CI = 0.19–0.97), users of hormone replacement therapy for less than 5 years (RR = 0.35; 95% CI = 0.15–0.82), and patients completing at least 12 months of treatment (RR = 0.49; 95% CI = 0.23–1.02). In contrast, in the subgroup of combined hormone replacement therapy users, tamoxifen seemed to have had no effect.

Vasomotor Symptoms 50% More Common With Tamoxifen

As for treatment side effects, vasomotor symptoms (such as hot flashes, night sweats, and vaginal dryness and discharge) were 50% more common in the tamoxifen group than in the placebo group, despite the concomitant use of hormone replacement therapy. However, headache was significantly more common in the group that received placebo.

Regarding the prespecified serious adverse events, there appeared to be no major difference between placebo and tamoxifen, including, respectively, coronary heart syndrome (6 vs 4), cerebrovascular events (2 vs 5), venous thromboembolism (2 vs 5), and uterine cancers (3 vs 1). However, there were more cases of endometrial polyps with tamoxifen than with placebo (27 vs 6); this side effect led to withdrawal of the drug in 10 women receiving tamoxifen and 2 women receiving placebo (P = .016).

The investigators concluded, “Our results are useful, as they provide a clue to reduce breast cancer, the major risk associated with hormone replacement therapy use, in a broad population composed of recently postmenopausal women.”

Andrea DeCensi, MD, of the Division of Medical Oncology, Ospedali Galliera, Genoa, Italy, is the corresponding author for the article in the Annals of Oncology.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.