Paul E Goss, MD, PhD, FRCP(CA), FRCP(UK)
Professor of Medicine, University of Toronto Director, Breast Cancer Research Program Princess Margaret Hospital, University Health Network Toronto, Canada

Edited comments by Dr Goss

Development of resistance to endocrine therapy

There are two types of resistance to endocrine therapy in invasive breast cancer — de novo resistance and acquired resistance. We’re only beginning to understand de novo resistance. Kent Osborne and his colleagues presented their ongoing research on HER2 overexpression, showing that through HER2, the mitogen activated protein (MAP) kinase pathways increase, and through MAP kinase, a number of receptors are phosphorylated.

Growth stimulation occurs through MAP kinase independently, but, in addition, MAP kinase seems to alter the estrogen receptor, making it more sensitive to both circulating estrogen and to the agonistic effects of tamoxifen. In a neoadjuvant study, Matt Ellis and his colleagues showed that patients who have HER2-positive, estrogen receptor-positive tumors are de novo resistant to tamoxifen but are sensitive to aromatase inhibitors. It’s probably partly through the MAP kinase pathway.

Development of aromatase overexpression

Endocrine resistance may occur in a number of ways. One is through estrogen receptor mutation at the breast cancer cell level and another is through the sensitivity of the cell to the estrogen content in and around the tumor cell. If one thinks about estrogen arriving at the breast cancer cell, there’s collaboration between the epithelial cell and the peritumoral stromal cells. Aromatase is functional in the peritumoral and the tumor cells, and it recruits the help of adjacent cells to create an autocrine loop of estrogen production. That loop has been shown to happen by estrogen deprivation and specifically through aromatase inhibitor therapies.

In cell culture you can evoke aromatase overexpression by long-term estrogen deprivation (LTED). The LTED cells will try to overcome the inhibition and upregulate aromatase. The same thing is true if you use aromatase inhibition in vivo in animal models. Tumor cells can also make substances that create alternative promoters of the aromatase gene. The aromatase gene is supposed to use specific promoters in the breast, and under influence of these substances, the ovarian promoter, for example, can be de-silenced, and the gene starts to function as it does in the ovary and drive aromatase production.

A phenomenon of aromatase overexpression in the face of aromatase inhibition and estrogen deprivation potentially occurs in the tumor and peritumoral cells. Couple that with a MAP kinase pathway being overexpressed, and you have increased sensitivity of the receptor resulting in exquisite sensitivity to estrogen and to the agonistic effects of any of the SERMs.

Optimal duration of adjuvant aromatase therapy

We’ve learned that prolonged therapy with tamoxifen may lead to a form of tamoxifen-acquired resistance, but we don’t yet know if this occurs with aromatase inhibitors. We also don’t know the correct duration of therapy with aromatase inhibitors. One clue might be the number of patients who relapse during therapy; another might be seeing what happens to patients at the cessation of adjuvant aromatase inhibitor therapy. That’s an unknown entity at this point, and we don’t yet have data from ATAC or any other aromatase trial to tell us what’s going to happen.

For years, investigators have talked about designing trials in which one switches back and forth between anti- and pro-estrogenic therapies to see if one could confound the cell. It has been shown that physiologic levels of estrogen can destroy tamoxifen-sensitive cells. Theoretically, the same thing could happen with aromatase inhibitors. If you supersensitize cells to estrogen and then increase the concentration of estrogen, it might be cytocidal, or cytostatic. Therefore, re-introducing estrogen therapy after aromatase inhibitors might work — and it might be effective at lower doses than previously used.

Utilization of agents to reverse resistance to aromatase inhibitors

It’s possible that prolonged aromatase inhibitor therapy alone will control most tumors, or we might find a point at which we need to introduce a resistance reverser. With de novo resistance, we might need to couple the inhibitor with a reverser from the beginning. Gefitinib (Iressa®) is an obvious reverser — it blocks the EGF receptor tyrosine kinase and it appears to reverse the acquired estrogen deprivation resistance that occurs — so an obvious combination would be an aromatase inhibitor with gefitinib. Whether they would be given in sequence or together from the beginning will have to be studied in clinical trials.

Currently there are no adjuvant trials evaluating that combination, but there are metastatic trials with gefitinib plus an aromatase inhibitor. There are also trials being designed in which patients failing on an aromatase inhibitor are either switched to gefitinib or continued on the aromatase inhibitor plus gefitinib.

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