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Tamoxifen: Risk of Rare Second Breast Cancer?

Treatment With Tamoxifen for Breast Cancer Patients Shouldn't Change, Researcher Says

By Miranda Hitti
WebMD Health News

Reviewed By Louise Chang, MD

Aug. 25, 2009 -- A new study links long-term use of the breast cancer drug tamoxifen to a rare but aggressive form of breast cancer, but experts say the findings shouldn't stop breast cancer patients from taking tamoxifen.

"We don't think that it overall changes the risk-benefit equation, in that women who are eligible to take this drug probably should still take it because of its proven benefit," researcher Christopher Li, MD, PhD, an associate member of the Fred Hutchinson Cancer Research Center in Seattle, tells WebMD.

"I think the worst thing that could happen, on a public health basis, with this paper is for patients and their doctors to look at this and say, 'Oh, this is a reason not to take tamoxifen.' Nothing could be further from the truth, for the reason that it obviously has enormous benefit," says Victor Vogel, MD, MHS, the American Cancer Society's national vice president for research.

Here's a look at the study Li and Vogel are talking about -- and why they stand by tamoxifen's use in breast cancer patients with "ER positive" breast cancer.

Most breast cancers are "ER positive," or estrogen receptor-positive. That means they grow when exposed to the hormone estrogen. Tamoxifen and other breast cancer hormone therapies thwart ER-positive breast cancer cells.

"ER negative" breast cancers, on the other hand, are rarer, tend to be more aggressive, and are more difficult to treat. They're not treated by tamoxifen or another class of estrogen-related breast cancer drugs called aromatase inhibitors, because ER-negative breast tumors aren't sensitive to estrogen.

Tamoxifen Study

Li's team studied data on nearly 1,100 Seattle-area women aged 40-79 who were treated for ER-positive breast cancer between 1990 and 2005. The group included 367 women who developed breast cancer in their other breast at least six months after their first diagnosis.

Li and colleagues interviewed all of the women and checked their medical records, noting any use of tamoxifen or other hormone therapies to help prevent breast cancer's return, and how long those drugs were used.

Most of the women took tamoxifen -- aromatase inhibitors are newer drugs and weren't available during many of the years studied. And most of the women didn't have another cancer develop in their other breast.

Women who used tamoxifen or other breast cancer hormone therapies were 60% less likely to develop an ER-positive cancer in their other breast, compared to those who never took tamoxifen.

But women who used tamoxifen for five or more years were about four times more likely than women who never used breast cancer hormone therapies to develop an ER-negative tumor in their other breast.

Tamoxifen use for less than five years wasn't linked to ER-negative breast cancer risk. The study didn't include any women taking tamoxifen to try to prevent a first breast cancer.

Researcher's Perspective

"Any sort of treatment has risks and benefits, and the benefits for tamoxifen are very clear, particularly with respect to reducing mortality. It also reduces the risk of recurrences," Li says.

Li counts increased risk of stroke and endometrial cancer among tamoxifen's known risks, and he says ER-negative cancer may be another risk.

But Li isn't calling for any change in how tamoxifen is used in breast cancer patients, or for taking tamoxifen for less than five years, because overall, the benefits still win out.

"The randomized trials looking at tamoxifen have very convincingly shown that full benefit of the drug is only obtained when it's used for five years," Li says. "I don't think they should change the recommendation that women should use it for the full five years."

Li also emphasizes that ER-negative breast cancers are rare, and that the study wasn't designed to show a woman's absolute risk of developing an ER-negative breast cancer.

"This is a relatively rare type of second cancer. In our study, only 25% were of this type," Li says. "So for the vast majority of cancers, [tamoxifen] is lowering the risk of second cancers. But for the smaller subset, this 25%, it's increasing the risk."

The study doesn't prove that tamoxifen caused any cancers, though Li's team weighed many other factors in analyzing the data.

Li and colleagues aren't sure how tamoxifen might raise ER-negative breast cancer risk, but they speculate that targeting ER-positive cells may allow ER-negative cells to take center stage. The researchers plan to study that further and to check to see if the findings also apply to another class of estrogen-related breast cancer drugs called aromatase inhibitors.

Second Opinion

Vogel, with The American Cancer Society, wasn't involved in the study, and he doesn't question the data analysis. But he notes that most women don't take tamoxifen beyond five years, and he's concerned that people may come away with the wrong impression.

"This should not be controversial, and actually, it's not new. This has been suggested before," Vogel says.

"But certainly none of the data has suggested that we stop using tamoxifen or change the way we apply it. ... The net benefit for tamoxifen is huge."

SOURCES: Li, Cancer Research, Sept. 1, 2009; vol 69: pp 6865-6870. Christopher Li, MD, PhD, associate member, Fred Hutchinson Cancer Research Center, Seattle. Victor Vogel, MD, MHS, national vice president, research, American Cancer Society. WebMD Medical Reference: "Types of Breast Cancer: ER Positive, HER2 Positive, Triple Negative."

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