Anastrozole Shows Preventive Advantages Over Tamoxifen After DCIS

Richard G. Margolese, MD

The first study to compare the efficacy and safety of tamoxifen versus anastrozole in women treated for ductal carcinoma in situ (DCIS) suggests that anastrozole may be the better choice for preventing the escalation of DCIS into invasive cancer.

Findings from the multicenter, phase III NRG Oncology/NSABP B-35 trial showed that after an average follow-up of 8.6 years, 114 breast cancers were detected in women taking tamoxifen compared with 84 among women who received anastrozole. Ten-year breast cancer—free survival was estimated to be 93.5% with anastrozole versus 89.2% with tamoxifen; however, a subgroup analysis showed that anastrozole was not superior to tamoxifen in women older than 60 years.

Richard G. Margolese, MD, lead study author and professor of surgical oncology at The Jewish General Hospital, McGill University in Montreal, Canada, presented these late-breaking findings during a press briefing May 30 at the 2015 ASCO Annual Meeting.

“The good news is, tamoxifen and anastrozole are both very effective, but it seems that women have better chances of staying well with anastrozole,” said Margolese. “Women should also consider differences in side effects when discussing treatment options with their doctors.”

The trial enrolled 3104 postmenopausal women who had been treated with lumpectomy and radiation after a diagnosis of hormone receptor—positive DCIS. Participants were randomly assigned to receive either tamoxifen (20 mg/day) and placebo, or 1 mg of daily anastrozole and placebo. Patients in both arms were eligible to receive the drugs for 5 years.

Margolese explained that the study’s primary objective was to decrease the number of breast cancer events, known as a breast cancer—free interval, defined by the researchers as “the time from randomization to any breast cancer event, including local, regional, or distant recurrence or contralateral disease, either invasive or DCIS.”

Although both drugs have long been used as hormonal therapy in patients with breast cancer, they have different mechanisms of action. Tamoxifen is an antiestrogen agent, while anastrozole is an aromatase inhibitor.

Participants in both cohorts were stratified by age (<60 years and ≥60 years), and the trial was carried out over 5 years. In women aged <60 years receiving tamoxifen (n = 722), 58 breast cancer events were reported versus 31 among the 725 women assigned to anastrozole (HR = 0.52; P = .003). Of 816 women aged ≥60 years in the tamoxifen arm, 56 breast cancer events occurred, versus 53 among the 814 women in that age group who were given anastrozole (HR = .95; P = .77). Eight deaths were reported due to breast cancer in the tamoxifen group and five in the anastrozole arm.

In women younger than 60 years, anastrozole’s benefit was “conspicuous,” said Margolese, “but in women older than 60, they all do well, and tamoxifen and anastrozole are of equivalent benefit.”

“We do not have a good explanation for this,” Margolese continued, noting that it will require more biologic investigation in clinical trials.

Margolese said that anastrozole performed better on all other secondary endpoints, but the differences were relatively small, and the only finding that reached statistical significance was the incidence of contralateral invasive breast cancer, which, he said, “again, was cut by almost half,” in the anastrozole cohort—36 events in the tamoxifen arm versus 20 with anastrozole (HR = 0.55; P = .03).

Investigators also assessed adverse events (AEs) known to be associated with each of the two hormone therapies. The main side effect of anastrozole is hastening of osteoporosis, and Margolese reported that the average annual rate of osteoporotic fractures in the anastrozole arm was 69 per 1000 patients versus 50 with tamoxifen. On the other hand, tamoxifen is associated with an increased risk of uterine cancer, and the average annual rate per 1000 women for uterine cancer (exclusive of hysterectomies) was 17 with tamoxifen compared with 8 with anastrozole.

Neither finding related to these two AEs achieved statistical significance, noted Margolese, adding that severe AEs are “uncommon with both agents—a little bit less common with anastrozole”&mdash;suggesting that it may be the preferred option for adjuvant treatment of DCIS, especially in women where there is concern about thromboembolism or uterine cancer.

The issue of how much treatment is appropriate for DCIS remains a vexing one in clinical practice. Although women with DCIS are at increased risk of developing invasive breast cancer, breast cancer—related death is uncommon in these patients when it is treated with radiation and lumpectomy, and both of the adjuvant hormone therapy options evaluated in this trial can cause side effects.

ASCO spokesperson Don S. Dizon, MD, who moderated the press briefing where the trial’s findings were announced, said these results are important because they provide doctors with additional ways to individualize therapy in this setting.

“Women with DCIS already have several great treatment options, and now they have one more. Aromatase inhibitors offer important advantages, but patients and their doctors should still consider the full range of options, including tamoxifen or even forgoing adjuvant treatment, as every approach carries its own risks and benefits,” he said.

The National Institutes of Health funded the study.

Margolese RG, Cecchini RS, Julian TB, et al. Primary results, NRG Oncology/NSABP B-35: a clinical trial of anastrozole vs tamoxifen in postmenopausal patients with DCIS undergoing lumpectomy plus radiotherapy. J Clin Oncol. 2015;(suppl; abstr LBA500).

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