High-dose toremifene as first-line treatment of metastatic breast cancer resistant to adjuvant aromatase inhibitor: A multicenter phase II study

Abstract

Abstract. There is currently no standardized therapy available for metastatic breast cancer in patients with aromatase inhibitor (AI)-resistant breast cancer. We conducted a prospective study to examine the efficacy and safety of high-dose toremifene (TOR) treatment for the first-line treatment of metastatic breast cancer following AI adjuvant therapy. A multicenter phase II study was designed (Registry no.: UMIN000000489). Inclusion criteria comprised hormone-responsive postmenopausal women who had received adjuvant AI postoperatively for >1 year and had relapsed during the treatment or within 12 months of completion of adjuvant therapy. Treatment comprised oral intake of 120 mg TOR once a day. The primary endpoint was objective response rate (ORR). The secondary endpoints were evaluations of clinical benefit (CB), progression-free survival (PFS) and toxicity. A total of 13 patients were enrolled. ORR was 7.7% (1/13) [95% CI, 0.2-36.0%]. In total, 7 patients (53.8%) had stable disease (SD), 5 of whom were long SD, and 5 patients (38.5%) experienced progressive disease (PD). The CB rate was 46.2% (6/13) [95% CI, 19.2-74.9%]. The median time to PFS was 5.9 months. No serious adverse events were observed. Patients with HER2-positive disease exhibited marginally poorer PFS (p= 0.08). Patients with PD had a relatively short duration of AI treatment in contrast to responders, who had a longer period of AI treatment (p=0.02). High-dose TOR as a first-line treatment following AI adjuvant therapy was effective and well tolerated. A longer duration of adjuvant AI therapy and negative HER2 overexpression may, with further studies, be beneficial as positive predictive factors for the effectiveness of TOR treatment.

Toremifene for Breast Cancer: A Review of 20 Years of Data

“…More recent data with toremifene should stimulate further research. Outstanding issues include: i) reasonably convincing phase III data and a meta-analysis suggesting similar efficacy and safety for adjuvant toremifene compared with tamoxifen in postmenopausal HR þ breast cancer 34,[36][37][38]63 ; ii) suggestions from a comparative trial that toremifene and letrozole showed similar efficacy as first-line therapy for postmenopausal patients with hormone receptor-positive metastatic breast cancer 39 ; iii) conflicting data in the ATAC trial, which showed potential antagonism between anastrozole and tamoxifen in combination vs. anastrozole alone, while the combination of toremifene and a different aromatase inhibitor, atamestane, showed results equivalent to those of letrozole 40 ; iv) suggestions that higher than standard doses of toremifene might be effective in patients for whom aromatase inhibitors have failed or even in patients progressing on tamoxifen [42][43][44]46 ; v) a controversial study from China suggesting that toremifene use in premenopausal patients in the adjuvant setting (in the absence of meaningful clinical trial data in premenopausal women) was not inferior to tamoxifen use. 51 Finally, despite clinical controversies surrounding alterations in CTP2D6 on tamoxifen outcomes, it is clear that the toremifene mechanism of action is independent of CYP2D6.…”

“…A second, prospective, multicenter study examined toremifene 120 mg daily in hormone-responsive postmenopausal women who had received adjuvant AI therapy postoperatively for > 1 year and had relapsed during the treatment or within 12 months of completion of adjuvant therapy. 43 Because of the difficulty with accrual, only 13 patients were enrolled in this study; however, the authors report 1 patient with partial response (7.7%) and 5 patients (38.5%) with stable disease > 6 months, for a clinical benefit rate of 46.2% with toremifene 120 mg. 43 In addition, Yamamoto et al retrospectively evaluated the effect of toremifene 120 mg day for the treatment of breast cancer in 83 women who relapsed on AIs. 44 Of these 83 patients, 12 patients (15%) achieved partial response and 24 patients (30%) had stable disease for 24 weeks, demonstrating clinical benefit in 45% of patients.…”

The Discovery and Development of Selective Estrogen Receptor Modulators (SERMs) for Clinical Practice

“…There are currently 2 main chemical classes of SERMs approved for clinical use: the first-generation triphenylethylene derivatives, tamoxifen [110] and toremifene [111, 112], which are used in the treatment and in the case of tamoxifen in the prevention of breast cancer [65, 113]; and raloxifene, a second-generation benzothiopene derivative indicated for the treatment and prevention of osteoporosis [29] and the reduction of breast cancer incidence in high risk post-menopausal women [31]. All 3 compounds also have beneficial effects on serum lipids, but are still associated with adverse effects such as hot flushes and an increase in the risk of venous thromboembolism (VTE).…”

A New Therapeutic Paradigm for Breast Cancer Exploiting Low Dose Estrogen-Induced Apoptosis

“…In 1979, Craig was to be 110 the opening speaker at the tamoxifen meeting in Sorrento, Italy. He was working in 111 Bern, Switzerland, and was scheduled to fly down on an Alitalia flight from Zurich 112 to Naples on the evening before his talk. Craig had to leave Zurich on the last flight 113 that evening, as he had a site visit at the Institute in Bern AU2 earlier in the day.…”

“…There are currently 2 main chemical classes of SERMs approved for clinical use: the first-generation triphenylethylene derivatives, tamoxifen [110] and toremifene [111,112], which are used in the treatment and in the case of tamoxifen in the prevention of breast cancer [65,113]; and raloxifene, a second-generation benzothiopene derivative indicated for the treatment and prevention of osteoporosis [29] and the reduction of breast cancer incidence in high risk postmenopausal women [31]. All 3 compounds also have beneficial effects on serum lipids, but are still associated with adverse effects such as hot flushes and an increase in the risk of venous thromboembolism (VTE).…”