Using the intratumoral aromatase xenograft model, we have observedthat despite long-lasting growth inhibition, tumors eventuallybegin to grow during continued letrozole treatment. In cellsisolated from these long-term letrozole-treated tumors (LTLT-Ca),estrogen receptor- (ER) levels were decreased, whereas signalingproteins in the mitogen-activated protein kinase cascade wereup-regulated along with human epidermal growth factor receptor2 (Her-2). In the current study, we evaluated the effect ofdiscontinuing letrozole treatment on the growth of letrozole-resistantcells and tumors. The cells formed tumors equally well in theabsence or presence of letrozole and had similar growth rates.After treatment was discontinued for 6 weeks, letrozole wasadministered again. Marked tumor regression was observed withthis second course of letrozole treatment. Similarly, in MCF-7Caxenografts, a 6-week break in letrozole treatment prolongedthe responsiveness of the tumors to letrozole. To understandthe mechanisms of this effect, LTLT-Ca cells were cultured inthe absence of letrozole for 16 weeks. The resulting cell line(RLT-Ca) exhibited properties similar to MCF-7Ca cells. Thecell growth was inhibited by letrozole and stimulated by estradiol.The expression of phosphorylated mitogen-activated protein kinase(MAPK) was reduced and ER and aromatase levels increased comparedwith LTLT-Ca cells and were similar to levels in MCF-7Ca cells.These results indicate that discontinuing treatment can reverseletrozole resistance. This could be a beneficial strategy toprolong responsiveness to aromatase inhibitors for patientswith breast cancer. [Cancer Res 2008;68(12):4518–24]
There is a study, being conducted in Europe only, to determine whether a 3 month on, 3 month off alternating cycle of AI's is superior to continuous treatment. It will be interesting to see the results, in light of this article.
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