Anastrozole Extends Breast Cancer Protection Once Stopped

Pam Harrison

December 18, 2019

SAN ANTONIO — For women at high risk of breast cancer, the protective benefit of taking 5 years of anastrozole, an aromatase inhibitor, to prevent the disease persists for at least another 5 years, a long-term follow-up of the International Breast Cancer Intervention Study II (IBIS-II) indicates.  

Dr Jack Cuzick

Study author Jack Cuzick, MD, Queen Mary University, London, United Kingdom, explained that another endocrine therapy, tamoxifen, has previously been demonstrated to have a similar extended effect in the prevention setting.

"It was crucial to look at this for the aromatase inhibitors as well," Cuzick told a press briefing here at the 2019 San Antonio Breast Cancer Symposium.

The results are now in, he said.

"With a median follow-up of 10.9 years, almost half of all new breast cancers were prevented with anastrozole after stopping treatment at 5 years, which is substantially greater than what we see with tamoxifen. So, anastrozole carries on producing continuing benefits right out to almost 12 years," he added.

Kent Osborne, MD, Baylor College of Medicine in Houston, Texas, said that the aromatase inhibitors appear to be somewhat more effective than tamoxifen in reducing breast cancer risk.

Osborne indicated that he is now more likely to counsel women at risk for breast cancer about anastrozole and its potential to reduce that risk, particularly women at very high risk.

"The aromatase inhibitors also don't cause endometrial cancer or blood clots," said Osborne, who moderated the press briefing and was not involved with the current study.

If patients develop arthralgias while receiving treatment with anastrozole, there are well-documented strategies that help provide relief, including acupuncture, and women are less likely to have hot flashes on an aromatase inhibitor than they are on tamoxifen, he noted.

Should patients do poorly on anastrozole, they can be switched to tamoxifen, which is usually (but not always) better tolerated, he pointed out.

Active Trial

For the active intervention portion of the trial, 1920 women ages 40 to 70 years at high risk for breast cancer were randomly assigned to anastrozole 1 mg daily and 1944 women were assigned to placebo.

Women were considered to be at high risk for breast cancer because of a positive family history, the presence of atypia, dense breasts, or lobular carcinoma in situ.

After 5 years on treatment, there was a 61% relative reduction in new breast cancers over the study interval, dropping from an absolute incidence of 4.6% in the placebo group to 1.8% in the active therapy group, which was highly statistically significant (P < .0001), Cuzick noted.

After approximately 11 years of follow-up, the incidence of breast cancer was still significantly lower among women who had previously taken anastrozole for 5 years, dropping from an absolute rate of 4.4% among women who took placebo to 3.5% for those who were on active therapy (P = .01).

"As we expected, the effect was stronger in estrogen receptor-positive cancers but, somewhat surprisingly, we found a nonsignificant effect in the reduction of new breast cancers in estrogen receptor-negative cancers, which was apparent in both treatment periods," he noted. 

Anastrozole also had a "big effect" in ductal carcinoma in situ (DCIS) — essentially precursor lesions, as Cuzick suggested — resulting in a 59% relative reduction in the incidence of new breast cancers overall.

Investigators did not have estrogen receptor assays on all the patients with DCIS, as it was not part of the required study protocol.

However, from the DCIS assays they did have, "we found a really dramatic, almost 80% reduction in new cancers — and that was seen in the first 5 years as well as subsequently over time," Cuzick said.

Adverse Events

Reported adverse events were "pretty reassuring", Cuzick indicated, with nothing serious emerging in the first 5 years or over the longer-term follow-up.

In terms of other cancers, there was an unexpected 28% reduction in nonmelanoma skin cancers in the active therapy group, although how an aromatase inhibitor might reduce skin cancer incidence remains a mystery, Cuzick pointed out.

"We had actually expected a reduction in endometrial cancer, but we did not see this because endometrial cancer is so estrogen-dependent," he added.

During the first 5 years on active treatment, 64% of women reported musculoskeletal arthralgias; 58% of women on placebo reported the same.

Arthralgias were most commonly reported during the first 3 to 6 months of receiving treatment with anastrozole, after which there were few additional new reports of the same side effects.

In fact, adherence rates to treatment during the 5 years women were involved in the active study were very similar (77% for those on placebo, 74.6% for those on anastrozole).

Importantly, "we saw no serious late events, no increase in fractures or cardiovascular events in women who took anastrozole," Cuzick said.

Notably, however, women were obliged to undergo DEXA scanning prior to study enrollment; they were encouraged to take a bisphosphonate if they were osteopenic and required to take a bisphosphonate if they were osteoporotic.

Cuzick noted that what he found "particularly striking" during the study was how common musculoskeletal effects were in the placebo group of the study.

"In a noncontrolled situation, all this gets attributed to treatment," he said.

"And one of the real challenges is that most of these effects that are being reported are not treatment-related," Cuzick noted, "so we have to be very careful in interpreting these findings because, in fact, the loss of continued treatment over the 5 years was very small at just 2.5%."

In 2013, the same research team reported that in the first 7 years of follow-up, anastrozole significantly reduced breast cancer incidence compared with placebo — and that it did so with very few side effects.

"Our new data show that after a median of 10.9 years of follow-up, there continues to be a significant reduction in breast cancer incidence," Cuzick reaffirmed.

This study was supported by AstraZeneca, Cancer Research UK, and the National Health and Medical Research Council Australia. Cuzick is a consultant for Myriad Genetics and his institution has received research funding from AstraZeneca. Osborne discloses that he has served on the advisory board for Genentech and AstraZeneca; as a consultant for Tolmar Pharma; and holds stock in GeneTex.

San Antonio Breast Cancer Symposium (SABCS) 2019: Abstract GS4-04. Presented December 12, 2019.

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