Presurgical Progesterone in Early Breast Cancer: So Much for So Little?

Abstract

(p 1072) Modern neoadjuvant endocrine therapy trials have confirmed clinical responses sufficient to downstage the tumor and avoid mastectomy in approximately 50% of postmenopausal women who are treated with aromatase inhibitors for large estrogen receptor (ER) –positive tumors. 2,3 Yet the concept that preoperative endocrine therapy might improve long-term outcome has until now not been tested clinically. This contrasts strikingly with neoadjuvant chemotherapy, for which several randomized trials have been carried out, and is a curious omission given that such therapy, if successful, would be simple to deliver and almost devoid of additional cost or resource implications. There are several plausible underlying rationales on which to base the concept that preoperative hormonal therapy affects long-term disease outcome. For example, it was shown in six different tumor types in a mouse model system that surgical excision of the primary tumor was associated with an increase in labeling index of metastases 24 hours later and an increase in their size. This effect was found to be associated with a transmissible humoral factor that caused identical kinetic changes when injected intravenously into recipients bearing similar tumors to the donor, and all of these effects could be blocked by tamoxifen (or chemotherapy) that was given before surgery. 4,5 Thus, tumor excision had a systemic stimulatory effect on distant disease that was negated by a preoperative endocrine agent in a manner that was independent of downstaging. More recently, it was shown in human breast cancers that preoperative aromatase inhibitor therapy administered for only 2 weeks reduced tumor cell proliferation by a mean approximately 75%, 6 and that this was accompanied by a profound reduction in the expression of multiple estrogen-dependent genes. 7 These effects could well be advantageous against tumor cells that may have been disturbed and released into the circulation during surgery. Trials that have compared preoperative with postoperative adjuvant chemotherapy have generally shown no significant differ