番茄社区

SAN ANTONIO -- Should anastrozole (Arimidex) be the top choice in pharmacologic primary prevention of breast cancer, based on IBIS-II trial results presented here? No, said most experts.

The aromatase inhibitor cut risk of developing a first primary breast cancer by 53% (2% incidence over 5 years versus 4% on placebo, P<0.0001) in that trial.

"We believe these results provide strong support for the use of anastrozole in high-risk postmenopausal women and that it should be the treatment of first choice for such patients," , of Queen Mary University of London, told attendees in presenting the results at the San Antonio Breast Cancer Symposium (SABCS).

Others disagreed.

"That's difficult to understand given that we have two other agents that have been shown to be effective, and you're comparison arm was a placebo and neither of those two other agents," , of the University of Toronto, countered from the audience at the session.

Cuzick then backpedaled and said the aromatase inhibitors as a class should be the first choice.

Even that was "quite a strong statement," commented session moderator Fabrice Andre, MD, PhD, of Institut Gustave Roussy in Villejuif, France.

"I think it was a little bit of an overstatement," conference co-chair , told 番茄社区.

"I don't entirely agree [with Cuzick]," added another co-chair, , of the University of Texas Health Science Center at San Antonio. "There should be some community discussion about the drug because there were some things that were kind of glossed over that are pretty well established [such as] side effects."

Comparing Results

There's no reason to expect any difference in effect among aromatase inhibitors based on comparisons done in women who already had a first breast cancer, said Osborne, of Baylor College of Medicine in Houston.

And in primary prevention specifically, the risk reduction with anastrozole was on par with what was seen with fellow aromatase inhibitor exemestane (Aromasin) in the MAP.3 trial, the researchers acknowledged in reporting the IBIS-II results online in .

Those results with those aromatase inhibitors have been stronger than reported with the selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene (Evista), but there are other factors to consider, namely side effect profiles, Osborne pointed out.

"I think there's a choice there," he said in an interview. "I think it's going to depend a lot on the patient, their characteristics, what is their bone health, do they have any pre-existing conditions that would suggest they would have more side effects on an aromatase inhibitor than on tamoxifen ... there are a whole bunch of factors."

The side effects of endometrial cancer and thromboembolism associated with tamoxifen weren't seen with either aromatase inhibitor.

Other side effects have been a concern with this class, particularly joint pain, bone loss, and vaginal symptoms.

"Side effects have always been the major barrier," Ravdin told 番茄社区.

The anastrozole findings suggested those might not be so bad as people think, Cuzick argued.

With a strategy of baseline bone density scans and bisphosphonates for at-risk women, IBIS-II showed only a tiny, nonsignificant elevation in fractures compared with placebo (9% versus 8%).

Vasomotor symptoms rates were "high" in both groups and not that much worse with anastrozole -- 57% versus 49% -- Cuzick pointed out.

He called it striking that musculoskeletal joint pain overall differed by so little, with a rate of 64% with anastrozole overall compared with 58% on placebo overall and just 4% and 2% absolute increases in moderate and severe arthralgia, respectively.

"So there's a very general perception that these drugs are very toxic and cause a lot of aches and pains," he told reporters at an SABCS press conference. But "most of these in uncontrolled situations are attributed to the drug. It's clear now that most of these aches and pains have nothing to do with aromatase inhibitors."

Cuzick suggested that this may help clinicians sell patients on primary prevention drugs, for which uptake has been low.

Moreover, there was a 40% relative reduction in nonbreast cancers in the anastrozole arm, driven by fewer skin and colorectal cancers. While this result was unexplained and in some ways contrary to expectations from other trials, it was highly significant and "merits further investigation."

Mixed Interpretations

However, experts questioned the low toxicity found in the trial and how well it might go over telling women the symptoms they're reporting are just aging.

The blinded comparison of anastrozole and tamoxifen in the landmark ATAC early breast cancer treatment trial did show extra arthralgia events, Ravdin pointed out. "I don't think you can dismiss it."

"Of course it's real," argued , a breast surgeon and director of the Breast Care Center at the University of California San Francisco.

When patients stop the drugs in the treatment setting they feel a lot better, and that's exactly what they're going to do despite being told what they're experiencing isn't a side effect, she pointed out in an interview.

"People will vote with their feet," she said. "Even if they think they're having a side effect they're not going stay on it, so the net effect is the same."

Cuzick, a statistician, acknowledged that it could be a dicey proposition for physicians.

"A major issue is how one actually conveys this to patients; that most of these aches and pains are not treatment related and are simply a function of age," he told attendees at the trial presentation.

Another concern raised by Osborne and Ravdin was the quality of adverse event reporting.

"Clinicians, as good as they are, are underreporters of toxicity," Ravdin explained. "Like sexuality issues: If you ask any gynecologist about aromatase inhibitors, he'll damn them. Yet clinicians will go, 'What are you talking about?' and that's because they neither ask nor does the patient volunteer."

How to Choose?

Anastrozole is a good option, and possibly even the best of the current options on average, Ravdin concluded.

"The whole story isn't quite in, but the idea that this is the best drug for everybody is ... probably not correct," he said.

The difference in side effect profiles between SERMs and aromatase inhibitors calls for individualization, he suggested. "For instance, a woman who is sexually active probably doesn't want to take anastrozole but would rather take raloxifene or tamoxifen."

Osborne agreed that no one strategy can be universally adopted.

"Maybe you would select an aromatase inhibitor prevention for certain patients and not in others, or try them on an aromatase inhibitor and if they don't tolerate it then switch them to tamoxifen or raloxifene," he proposed. "It's nice that we have a choice."

Just having another option isn't necessarily going to help women that much, Esserman argued.

What's really needed is a biomarker to demonstrate that a given woman is benefiting from endocrine treatment, similar to blood pressure in heart disease prevention, she told 番茄社区.

"Let's find the intermediate endpoint to show that these drugs are working before we put someone on it for 5 years, because that's what's going to motivate people: 'A) I'm truly at risk and B) I'm going to benefit and here's my demonstration that I am particularly going to benefit'," Esserman said. "That's the right paradigm for prevention."

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