Implementations of aromatase inhibitors either as monotherapy or in sequence with tamoxifen for adjuvant therapy has challenged our algorithm for endocrine treatment of postmenopausal women in the metastatic setting. Previously, for patients being treated with tamoxifen (or not having adjuvant endocrine therapy) first-line treatment in metastatic disease should mean treatment with one of the new third-generation aromatase inhibitors, anastrozole, letrozole, or exemestane. Alternatively, patients relapsing more than 1 year following completion of tamoxifen therapy were rechallenged with the same compound. While currently most physicians would agree that patients not being exposed to any of the novel third-generation aromatase inhibitors should receive one of these compounds as first-line therapy in metastatic disease, we need to develop algorithms with respect to how to handle patients being exposed either to an aromatase inhibitor as monotherapy, or tamoxifen followed sequentially by an aromatase inhibitor, in the adjuvant setting.
Taking into account the high efficacy and low toxicity of third-generation aromatase inhibitors as well as tamoxifen, we believe the following approaches to be reasonable:
Considering those patients having an aromatase inhibitor as mono-therapy in the adjuvant setting, first-line therapy in metastatic breast cancer could be tamoxifen-independent of the time frame between terminating treatment and time of relapse. For those being exposed to both treatment options in the adjuvant setting (e.g., tamoxifen followed by an aromatase inhibitor), provided they relapse >1 year after terminating treatment with an aromatase inhibitor, one of these compounds could be explored as first-line treatment. For those relapsing within a time frame of 1 year or less after terminating adjuvant therapy or during therapy, while evidence is currently lacking, it may be reasonable to expect that some of these patients terminating tamoxifen several years earlier could still be sensitive to that treatment approach.
An interesting question is whether patients relapsing after treatment with an aromatase in the adjuvant setting should be treated with a different compound, preferentially a compound belonging to the "alternative class" (steroidal versus nonsteroidal compounds) in the metastatic setting. While direct evidence is lacking, based on the findings of lack of complete cross-resistance between these compounds in the metastatic setting (72-74), this seems to be a natural approach.
While the final role of fulvestrant in metastatic disease remains to be settled, this drug certainly offers an interesting treatment approach. Although fulvestrant was found to be not significantly different from anastrozole regarding efficacy in the advanced setting (75), it has not been compared to any of the other aromatase inhibitors. So far, the only study comparing two aromatase inhibitors (letrozole and anastrozole) on a head-to-head basis found an increase with respect to response rate for letrozole but no difference regarding the primary endpoint time to progression (76). Importantly, this study was conducted in the second-line setting, in which it may be difficult to document a difference between two compounds. Looking at studies conducted with anastrozole as well as letrozole versus tamoxifen in metastatic disease or for primary (neoadjuvant) therapy in advanced breast cancer (40, 77-79), evidence favoring letrozole over tamoxifen is consistent. In contrast, evidence favoring anastrozole compared to tamoxifen is weaker, with several studies reporting equal efficacy for anastrozole and tamoxifen. On the other hand, there is little evidence so far from the adjuvant studies indicating a major difference between the two aromatase inhibitor (80, 81), thus, the "jury is still out."
While the aim of developing fulvestrant was to develop a compound causing "total estrogen blockade" with no additional agonistic effects, interestingly recent evidence suggests patients failing on fulvestrant therapy may not be totally refractory to alternative forms of endocrine therapy (82, 83). Based on in vitro data (84), the potential of combining fulvestrant with an aromatase inhibitor is currently an issue for clinical studies.
In summary, fulvestrant definitely has a role in treatment of advanced breast cancer, but there is currently limited data favoring its use over tamoxifen or third-generation aromatase inhibitors. At this stage, fulvestrant more seems a natural treatment option for patients whose tumors have become resistant to the other two treatment options (tamoxifen and Als).
We still lack evidence regarding efficacy of progestins in high-doses for patients becoming resistant to the third-generation aromatase inhibitors. In contrast, in a pilot study we found significant clinical effects using diethylstilbestrol (DES) 15 mg daily in patients failing aromatase inhibitors (8). Side effects in general were acceptable, and estrogens in high doses are currently evaluated in larger studies. We consider additive treatment with estrogens in high-doses a feasonable treatment alternative for advanced breast cancer. Compared to fulvestrant, with the data currently available we may consider these treatment options equal; their use based on individual patient preferences and side effects.
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