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Oncology Times:
doi: 10.1097/01.COT.0000445621.61652.d8
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IBIS-II Results: Anastrozole Effective as Breast Cancer Preventive

Susman, Ed

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After seven years, treatment with the aromatase inhibitor anastrozole appears to reduce the risk of breast cancer in woman at high risk of the disease by more than 50 percent when compared with placebo, according to data reported at the San Antonio Breast Cancer Symposium.

“These exciting results from our prevention trial provide rather convincing evidence for the effectiveness of anastrozole,” Jack Cuzick, PhD, Director of the Wolfson Institute of Preventive Medicine at Queen Mary University in London, said at a news briefing at the meeting.

“After seven years of follow-up, 5.6 percent of the placebo population were diagnosed with cancer—that works out to be a projected rate of about eight percent over a 10-year period. We reduced that by just over 50 percent to 2.8 percent. If we focus just on invasive, estrogen receptor-positive cancers, the relative benefit was similar and a little larger.”

In the placebo group, 3.3 percent of the women were diagnosed with these dangerous cancers compared with 1.4 percent of the women taking anastrozole—an absolute reduction of about two percent, the data showed. “These results are as good as we could have hoped for,” he said.

“We reduced the overall number of breast cancers from 85 to 40 with anastrozole. That was a 53 percent reduction in all cancers. It was very striking for DCIS, where 20 cancers were observed among placebo patients and that was reduced to six—a 70 percent reduction—among women on anastrozole.

“For invasive cancers we saw a 50 percent reduction—64 cancers in the placebo arm versus 32 in the anastrozole-treated patients. In estrogen-receptor positive cancers we saw a 58 percent reduction—from 47 cancers in the control group and 20 cancers in the anastrozole patients. For estrogen receptor negative invasive cancer there were 14 cases among controls and 11 among patients on anastrozole, a non-significant difference. We didn't expect to see a difference in this group, and it is probably a chance finding.”

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No Increase in Bone Fractures

He also noted that the reduction in breast cancer did not appear to come at the cost of increased adverse events—particularly in the rate of fractures.

“There is only a small increase in fractures—which is not significant, and that is very reassuring,” he said.

He reported that 8.5 percent of women on anastrozole experienced fractures during the trial compared with 7.7 percent of the women assigned to placebo.

“There were significant increases in musculoskeletal adverse events with anastrozole, but there also was a very high rate seen with placebo, and it is very clear now that most of these aches and pains have nothing to do with aromatase inhibitors,” Cuzick said.

“We believe these results provide strong support for the use of anastrozole as the first treatment of choice in high-risk postmenopausal women who want to reduce their risk of breast cancer. Long-term follow-up is essential, and we will continue to do that, going out to 10 and even 20 years. It will be important to get the full picture, but the early results are very, very positive.”

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Class Effects

In response to questions from reporters, Cuzick suggested that the findings were likely a class effect of the aromatase inhibitors. Interestingly, he illustrated that other cancer occurrences were also markedly reduced among women taking anastrozole. “We found a very large reduction in other cancers, and we don't quite understand this—which is a reduction in other cancers of about 40 percent.

There were 70 other cancers among the patients on placebo and 40 cancers in the anastrozole patients. The reductions were mainly skin cancers—about 50 percent (27 skin cancers, including seven melanoma) occurred in the placebo group, compared with 14 skin cancers, including four melanomas, in the anastrozole patients. Eleven gastrointestinal cancers occurred among the placebo patients compared with three in the anastrozole group.

“This is another exciting possibility, that this may have an effect on other cancers, which we will continue to explore,” Cuzick said.

In the International Breast Cancer Intervention Study-II (IBIS-II), his team enrolled 3,864 postmenopausal women age 40 to 70 who were considered at increased risk of breast cancer mainly due to family history. Patients were enrolled from 2003 to 2012.

JACK CUZICK, PHD
JACK CUZICK, PHD
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A total of 1,920 women were assigned to receive 1 mg of anastrozole daily and another 1,944 were assigned to placebo. The patients were assessed twice in the first year and then once every year. They underwent mammography at baseline and once every two years, had blood work taken at baseline and then at 12 months and after five years, and also had a bone density scan at baseline.

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Well Tolerated

“Compliance was very good, and one of the points in this trial is that anastrozole was very well tolerated,” Cuzick said. Overall, 72 percent of the placebo patients remained on study compared with 68 percent of the patients on anastrozole.

One of the trial co-investigators, John Forbes, MBBS, Professor of Surgical Oncology at the University of Newcastle in Australia, said there is not enough awareness among “the millions of women potentially able to benefit from this study—They are not attending cancer hospitals and high-risk clinics necessarily, but they are under the care of a community physician or general practitioner.

“There is a big task to educate the community about what is there,” he said. “Anastrozole is not compulsory but it is an option for choice. As a clinician to have another choice for prevention is very important for us.”

He noted that because the compliance rate indicated that at least 25 percent of the women were not taking the treatment but were included in the analysis, “the true effect of the drug may be even greater than what was reported.”

Cuzick said that tolerance and adverse events were concerns of the trial investigators: “We were concerned that aromatase inhibitors like anastrozole would actually increase the fracture rate because they lead to bone density loss. We were very careful in this trial to make sure that women got a bone density scan before they started. If they had low bone density, they got bisphosphonate treatment and careful monitoring. With that we got a very, very tiny increase in fracture rates that were not even statistically significant.”

Musculoskeletal aches and pains were about 10 percent more common among women on anastrozole compared with those on placebo as were arthalgias.

“The striking finding in this is that in a placebo-controlled trial, that there was an extremely high level of aches and pains and arthralgias in the placebo patients—nearly 58 percent of placebo patients complained of these problems compared with 64 percent of patients on anastrozole,” Cuzick said.

“There is a general perception that these drugs are very toxic and cause a lot of aches and pains, but this study appears to show that these complaints have nothing to do with the drug, but are just a reflection of the postmenopausal era in which women get aches and pains, as do men.”

Joint stiffness and carpal tunnel syndrome were experienced about 50 percent more often among women on anastrozole, which Cuzick suggested were reflective of aging. Hot flashes also occurred about 15 percent more often among the women on anastrozole, occurring in about half the placebo patients and in about 57 percent of the anastrozole patients. “These were small increases, but they are real increases,” he said.

More anastrozole patients also reported dry eyes as a symptom than did women on placebo, and the anastrozole group also had more hypertension.

There were 35 deaths in the study—two related to breast cancer. “There was nothing striking about the deaths,” he said.

“Two other anti-hormone therapies—tamoxifen and raloxifene—are used by some women to prevent breast cancer, but these drugs are not as effective and can have adverse side effects, which limit their use.”

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Edith Perez

Asked for her opinion, Edith Perez, MD, the Serene M. and Frances C. Durling Professor of Medicine at the Mayo Clinic Jacksonville in Florida, called the data consistent with the knowledge that anti-estrogen therapies decrease the risk of hormone receptor-positive breast cancer.

“Although tamoxifen and raloxifene are approved by regulatory agents for this purpose, these new data with anastrozole are fairly similar to those with exemestane as per the MAP-3 trial published now a few years back in the New England Journal of Medicine. I wish that regulatory agencies could look at these data and approve the use of these agents for reducing the risk of breast cancer, instead of requiring more studies.”

Cuzick said the plan is to continue following the IBIS-II Prevention participants for at least 10 years, and hopefully much longer. “We want to determine if anastrozole has a continued impact on cancer incidence even after stopping treatment, if it reduces deaths from breast cancer, and ensure that there are no long-term adverse side effects.”

The study was supported by Cancer Research UK, the National Health and Medical Research Council of Australia, AstraZeneca, and Sanofi-Aventis; Cuzick noted in his disclosure that he is on the speaker's bureau for AstraZeneca.

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iPad Extra!

In a video interview on the iPad edition of this issue with OT reporter Dan Keller, Dr. Cuzick elaborates on the clinical results of the trial, noting that anastrozole appears to be more effective and have fewer side effects than tamoxifen or raloxifene.

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If you are not yet receiving our iPad issues, download the free Oncology Times app from the App Store today! Visithttp://bit.ly/OT-iPadApp, search in the App Store, or follow the link ononcology-times.com.

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