Anastrozole Halves Breast Cancers in Prevention Study

Eventual mortality benefit doubted

Kate Johnson

December 12, 2013

SAN ANTONIO, Texas — The aromatase inhibitor anastrozole cut the incidence of breast cancer in half among high-risk postmenopausal women who took it for 5 years, researchers announced in the first results of the International Breast Cancer Intervention Study II (IBIS-II) trial.

After a median follow-up of 5 years, 2% of women in the anastrozole group and 4% in the placebo group had developed breast cancer (hazard ratio [HR], 0.47; P < .0001).

The findings, reported here at the 36th Annual San Antonio Breast Cancer Symposium (SABCS) today and published simultaneously in the Lancet, offer "strong support" for anastrozole as the first choice for chemoprevention of breast cancer in high-risk women, announced lead investigator Jack Cuzick, PhD, chair of the IBIS-II Steering Committee and director of the Wolfson Institute of Preventive Medicine at Queen Mary University in London, United Kingdom.

This strong statement, touting anastrozole over established preventive medications, drew some critical reaction from members of the audience.

"I wouldn't go that far," said Pamela Goodwin, MD, a senior researcher from Lunenfeld-Tanenbaum Research Institute at the Mount Sinai Hospital in Toronto, Ontario, Canada.

"One drug can't be claimed to be better unless they are compared head to head in the same trial," she told Medscape Medical News after the presentation. "Anastrozole was better than placebo in IBIS-II, and the authors felt benefits outweighed risks. And that was fine, but cross-study ‎comparisons are problematic because populations differ between studies."

Dr. Cuzick later told Medscape Medical News that the reported benefits of anastrozole are greater than those of the existing breast cancer prevention drugs tamoxifen and raloxifene, and with fewer adverse effects.

"The important fact is that gynecological symptoms including endometrial cancer and bleeding are not associated with [anastrozole]. Nor is there any increase in blood clots or thromboembolic events," he said, referring to adverse events seen with the other chemoprevention agents.

In addition, although the study's 5-year follow-up is too short to determine the drug's effect on breast cancer mortality, "we have seen a reduction in high-grade tumors, which does suggest we will get an effect on deaths," Dr. Cuzick noted.

However, in an editorial accompanying the study, David Cameron, MD expressed doubts. "The likelihood of an eventual breast cancer mortality benefit seems small," writes Dr. Cameron, who is from the Edinburgh Cancer Centre and Western General Hospital in Edinburgh, Scotland.

"The majority of the cancers detected in IBIS-II were found through screening, meaning they were low-risk," he told Medscape Medical News in an interview at the conference. "The chance of dying of a screen-detected cancer is considerably less than dying of a symptomatic cancer, so it looks as if anastrozole is preventing curable cancers. What we don't know is how many premature deaths it's preventing. This is another trial offering another option but not, in my view, any more clarity in terms of the risk–benefit balance."

High-Grade Tumor Frequency Cut With Anastrozole

IBIS-II included 3864 postmenopausal women aged 40 to 70 years who were considered high risk for developing breast cancer because of family history, atypia/lobular carcinoma in situ, or breast density.

The women were randomly assigned to receive either anastrozole 1 mg daily (n = 1920) or matching placebo (n = 1944).

Subgroup analysis showed a greater reduction in ductal carcinoma in situ (hazard ratio [HR], 0.30) and a 50% reduction in all invasive disease, mostly in estrogen receptor (ER)-positive tumors (HR, 0.42; P = .001), with a nonsignificant effect on ER-negative tumors (HR, 0.78)

An "intriguing" finding was that anastrozole reduced the frequency of high-grade tumors (HR, 0.35) more than that of low-grade ones (HR, 0.86), said Dr. Cuzick "Although highly significant, this finding could have been a result of chance, because other indicators of aggressive or fast-growing tumors (eg, node positivity and large tumor size) were not differentially affected," Dr. Cuzick and coauthors write.

Another "surprising" finding, according to the authors, was a "very large" reduced frequency of cancers other than breast cancer in the anastrozole group (risk ratio [RR], 0.58), notably gastrointestinal (P = .05) and skin (P = .07). "This is another exciting possibility, that this may have an effect on other cancers, which we will continue to explore."

Regarding adverse effects, vasomotor symptoms were common in both groups but were significantly more common in the anastrozole group (P < .001), as were musculoskeletal aches and pains (P = .001), noted Dr. Cuzick. In addition, hypertension was increased in the anastrozole group.

"Mostly the aches and pains associated with estrogen loss were similar to [what is seen] with tamoxifen, and when you compare [them with] placebo, most are not drug-related, The major side effect that we were concerned about was for fractures, but it looks like we know how to control that by just doing a bone-density scan upfront [and bisphosphonate treatment if necessary]," Dr. Cuzick said.

He emphasized that a major challenge is to convince the public that cancer prevention with anastrozole is safe.

"There is a major issue here in terms of the perception that these drugs cause a lot of toxicity, and the concept of actually preventing cancer does not sit well with the general population," he said. "I think there's a lot to be done in terms of education to make people aware that there are effective means of reducing the risk of breast cancer by more than 50%, and of course if you have a toxicity, you simply stop."

John Forbes, MD, from the Australian New Zealand Breast Cancer Trials Group, Calvary Mater Newcastle, University of Newcastle, Waratah, and a coinvestigator on the study, agreed.

"I'm a clinician, and I see a lot of patients who are at high risk. To have another choice is very important for us," he said. "There is not a lot of awareness among the millions of women potentially able to benefit from this drug. They're not attending cancer hospitals and high-risk clinics, necessarily. There's a big task to educate the community."

This study was supported by funds from Cancer Research UK, the National Health and Medical Research Council of Australia, AstraZeneca, and sanofi-aventis. Dr. Cuzick is on the speaker's bureau for AstraZeneca.

36th Annual San Antonio Breast Cancer Symposium (SABCS): Abstract S3-01. Presented December 12, 2013.