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Edited comments by Dr Jordan
Tamoxifen resistance
Our model of drug resistance applies to all of the selective estrogen receptor modulators (SERMs), but tamoxifen is the example we have used. If estrogen is driving the tumor cell, tamoxifen will block that tumor's estrogen-stimulated growth for many years. Tamoxifen provides a strong antitumor effect in the patient with ER-positive disease.
Over the last 10 years, we've learned that there are things we wouldn't necessarily have anticipated happening at the cellular level. For example, with continuous tamoxifen exposure, one form of drug resistance is tamoxifen-stimulated growth. Hence, tamoxifen is exploiting the estrogen-receptor mechanism and causing these tumors to grow.
How does this happen? We think there is cell-surface signaling. The cell-surface receptors (e.g., epidermal growth factor receptor and HER2) produce a phosphorylation cascade. These cell-surface receptors are activated, and they transfer the phosphorylation of proteins into “superactivation” of the tamoxifen-estrogen-receptor complex; hence, turning it from an antiestrogenic complex to an estrogen-like complex that will promote tumor growth. This new way of looking at drug resistance, where an inhibitor stimulates cell growth, gives us insight into the future use of these agents.
During this first phase of drug resistance, if tamoxifen is discontinued, the tumors do not grow. In the clinical setting, tamoxifen-supported growth of advanced breast cancer has been seen for many years, and there can be a tamoxifen-withdrawal response. Tamoxifen is stopped, and the tumor stops growing. Tony Howell reported this in a series of patients in the Annals of Oncology in the early 1990s. In this type of drug resistance, a woman's endogenous estrogen can also bind to the estrogen receptor and take over where tamoxifen left off. An aromatase inhibitor is a good alternative as second-line therapy after tamoxifen resistance occurs, because it reduces the woman's endogenous estrogen.
We've now described a second phase of tamoxifen resistance; if tamoxifen is stopped, instead of estrogen stimulating growth, it destroys the tumor cells. This is a laboratory model that we've replicated in many other breast cancer cell lines and endometrial cancer cell lines. Richard Santen also found the same thing with estrogen deprivation of breast cancer cell lines. If estrogen is taken away from breast cancer cell lines for a couple of years and then small amounts of estrogen are put back, the cells go through apoptosis and die. The general principle is supersensitivity. As part of the process of drug resistance, these cells become supersensitized to the negative effects of estrogen. They turn on death pathways and turn off survival pathways.
We've also started to describe a third form of drug resistance — the ER-positive breast cancer cell that will grow spontaneously after five or 10 years of antihormonal therapy. Fulvestrant, letrozole, anastrozole, tamoxifen or raloxifene will not work in these animal models. Nothing will control the growth of these tumor cells; they grow relentlessly. But if postmenopausal levels of estrogen are given to these animals, the tumors melt away. The survival mechanisms of the cells are so strong that they have subverted anything an antihormonal agent can do. The cells have learned to grow without any stimulus, and they appear to be hormone-independent. But estrogen can still destroy these tumor cells quite effectively by switching on death receptors and switching off survival pathways.
Extended endocrine deprivation
Clinically, there are a few sporadic reports that estrogen will destroy tumor cells after extended endocrine withdrawal. In the laboratory, we've shown that extended endocrine withdrawal followed by estrogen therapy will kill 90 percent of the tumors. Of the 10 percent of tumors that re-grow, when we transplant those, endocrine therapy works again. In women who have had extended endocrine therapy, we could plan clinical trials that utilize an estrogen “purge,” and then consider antihormonal therapy to maintain patients for a much longer period. Obviously, we'd have to try this in women with advanced disease as an interface before we go to chemotherapy.
In a retrospective analysis reported in Breast Cancer Research and Treatment 2001, Per Lonning and Tony Howell found that diethlystilbesterol (DES) produced four complete responses in 32 patients with ER-positive advanced breast cancer that had been treated with sequential endocrine therapies (i.e., tamoxifen and aromatase inhibitors). One of the complete responses lasted well over a year. These were women whose only other choice was chemotherapy.
After prolonged endocrine therapy, if drug resistance has built up and the survival pathways are developed, the survival pathways will defend against the effects of chemotherapy. Therefore, the apoptotic responses that we anticipate with chemotherapy are potentially going to be blunted by the establishment of this long-term survival pathway with antihormonal therapy.
Can we change the environment? High doses of phytoestrogens may be able to pre-prime these cells for chemotherapy. This would start destruction of the survival pathways that could be built upon more effectively with chemotherapy. For 10 years, we've been working on how to go back and exploit the target —the estrogen receptor, as I call it, “the gift that keeps on giving.”
Mechanism of action for DES
Dick Santen's paper in theJournal of the National Cancer Institute helped us understand why high-dose estrogens have an antitumor effect. He has been very interested in aromatase inhibitor drug resistance. He asked the questions: Is drug resistance to an aromatase inhibitor going to be related to supersensitivity to estrogen? Are very small amounts of estrogen going to keep these tumors growing?
In his paper, Santen said, “This is giving us our first insight into what happens with DES.” He made the argument that older, postmenopausal women in their seventies have been estrogen-deprived for a long time, and DES worked great in those ER-positive patients. In contrast, DES hardly worked in perimenopausal women in their fifties. Hence, long-term estrogen deprivation is required for estrogen to cause this death cycle.
Predicting which patients will respond to estrogen
We need to develop some sort of test to ensure that we give estrogen to the right patients. If we can screen various human tumor models, gene array profiling may be able to tell us with a high probability which cells estrogen will kill and which cells estrogen will allow to survive. Maybe we can get some idea in advanced disease, where there is accessible tissue, whether gene profiling will work.
Another idea would be to evaluate patients with noninvasive techniques. In a patient treated with long-term endocrine therapy who is probably in the “estrogen death scenario,” maybe PET or some other detection technique can monitor over a period of weeks whether there is any change in the viability of the tumor when their diet is changed to high-estrogen-containing foods —phytoestrogens. Once no growth is documented with this dietary change, then the patient may be treated with estrogen and appropriate chemotherapy to obtain a far bigger cell kill than imagined.
Hormonal therapy after disease progression on an aromatase inhibitor
I wouldn't rush off and give those patients DES. There's laboratory data suggesting that destroying the estrogen receptor with fulvestrant works after long-term estrogen deprivation with anastrozole. In cell culture, tamoxifen works, but I would use fulvestrant because of the possibility that cell-surface signaling is enhanced by long-term estrogen deprivation.
Selecting drug therapy in the future
We need to examine breast tumors and determine the top ten things that go wrong with the cell-surface signal transduction pathways. Then, we will be able, better than ever before, to profile patients. We'll be able to pick a combination of agents to prevent cell survival and promote cell death. In the next 10 years, that's going to be a reality. It's not going to be the same drug for everybody. There will be 10 drugs that we can apply effectively, and we'll choose three or four for a particular patient that will promote apoptosis and close down as many cell-survival pathways as possible.
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