Some women who would benefit from hormonal therapy for breast cancer are not getting it because they have been found to be estrogen receptor and progesterone receptor negative when they are, in fact, at least weakly positive for both receptors.
"The testing has to be done right, and its not," said D. Craig Allred, M.D., of Baylor College of Medicine, Houston, a pathologist who has extensively studied the subject. At the San Antonio Breast Cancer Symposium, Allred decried the number of false negatives that he said were arising from failure of laboratories to validate the assays they were using.
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This switch to immunohistochemistry from ligand binding assays did have many positive aspects, he said. The former is cheaper and easier to do, and it does not use radioactivity, which was required for the ligand binding assay. On the other hand, the ligand binding assay was well validated and done the same way all over the country.
Now, he said, there is no uniformity in the antibodies used, all of which have different sensitivities. He said that the error rate when it comes to ER positivity "is not smaller than 5%, and thats based on this argument: Almost all the labs in the country have arbitrarily decided that 10% estrogen-positive tumor cells is the lowest level they would accept for ER positivity."
Yet, in a study of some 1900 women at Baylor, Allred found that women with ER positivity in the range of only 1% to 9% were responsive to hormonal therapy.
He said there are a number of reagents out there. After testing several, his laboratory chose the antibody 6F11, which is specific for ER alpha.
He added that it is still unclear what the newly found ER beta contributes to breast cancer. He said the old ligand binding assay tested for both, and some of the IHC assays test for one versus the other, depending on the specificity of the antibody. Whether ER beta is important in breast cancer is unknown, but it is being investigated, he said.
He said that, in its most recent statement, the College of American Pathologists listed ER and progesterone IHC as approved for routine use, but it did not specify how the tests should be used, and it acknowledged there were many problems doing them. However, this may change. The college is considering setting up educational programs and perhaps guidelines to improve accuracy.
Richard Gelber, Ph.D., of the Dana-Farber Cancer Institute and Harvard University, Boston, concurred that hormone receptor positivity and negativity have not been well validated. His study group, the International Breast Cancer Study Group, has started to consider three categories of cases for data analysis: receptor absent with 0% stained, receptor low with 1% to 9% stained, and receptor positive, with 10% or more cells stained.
Deny Few
Gelber said that he believes that the key is to deny endocrine treatments only to patients for whom the assay shows absolutely no staining whatsoever. "We feel that even a hint of staining may be a sign that the disease may have some degree of endocrine treatment responsivity," he said.
While Allred and Gelber said they think that women are being harmed by errors in interpretation, not everyone agrees. Myles Brown, M.D., associate professor of medicine at Harvard, and also at Dana-Farber, believes that while there are problems with standardization of assays, "the current assays predict pretty well for response to endocrine therapy, so if there were a lot of women being misclassified, that wouldnt be the case." As far as assays for ER beta, however, he agreed that there are a large number of unvalidated assays.
All three investigators agree that it would be nice to have some way of predicting when women who do respond to hormonal therapy, such as tamoxifen or an aromatase inhibitor, start failing to respond. A recent study showed that after an average of 5 years, women on tamoxifen to prevent recurrence no longer benefit from taking the drug. The other question they ask is, would switching the women to another drugperhaps an aromatase inhibitor if they were on tamoxifen, or perhaps another kind of selective estrogen receptor modifierthen cause them to respond again? The question remains unanswered.
Whats Behind It
But Donald McDonnell, Ph.D., of Duke University, Durham, N.C., explained that the reason women on tamoxifen eventually fail is that the tamoxifen drives the receptor into a different shape, which eventually the cells learn to recognize. "Our model right now is that the surface on the receptor thats presented in the presence of tamoxifen allows the receptor to interact with transcription co-activators."
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"But what we actually need, and we dont yet have, is a pure competitive antagonist . . . Something that would bind to the receptor and rather than changing its shape, just fill the hole."
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