Benefit With Aromatase Inhibitors in the Adjuvant Setting for Postmenopausal Women With Breast Cancer

Henning T. Mouridsen, MD, PhD; Nicholas J. Robert, MD

Disclosures
In This Article

Early Sequential Adjuvant Trials

ICCG 96 (IES) -- International Collaborative Cancer Group (Intergroup Exemestane Study)

Study Design. Exemestane has been evaluated in the early sequential adjuvant setting in a large, double-blind, randomized trial designed to compare 2 to 3 years of exemestane with 2 to 3 years of tamoxifen, in patients who had already received tamoxifen for 2 to 3 years. Patients (N = 4742) were postmenopausal women with ER+ early breast cancer who were disease-free after initial tamoxifen therapy. They were randomized to continue tamoxifen or to switch to exemestane (25 mg/d), with treatment continued for a total 5 years of adjuvant therapy (Figure 3).

The primary end point was DFS, based on the first recurrence of breast cancer at any site or occurrence of new contralateral breast cancer or death without recurrence. Secondary end points were OS, incidence of contralateral breast cancer, and long-term tolerability. Substudies were designed to evaluate bone metabolism, QOL, and endometrial changes.[6]

Results. Patient characteristics were well balanced between the 2 treatment groups ( Table 7 ).[37] After 30.6 months' median follow-up and 449 events, the second planned analysis showed a 32% reduced risk of recurrence in the exemestane sequential arm ( Table 8 ).[37] Estimated 3-year DFS was significantly higher in the sequential exemestane group (91.5%) compared with the group that continued on tamoxifen (86.8%). Subgroups with node-negative vs node-positive disease and subgroups with or without prior chemotherapy had similar reductions in risk associated with sequential treatment with exemestane.[37] In addition, the sequential exemestane group had significantly reduced risk of distant disease (HR 0.66; P = .0004) and contralateral breast cancer. Overall survival was not significantly different between the 2 groups (HR 0.88; P = .37). In an updated analysis, now with 37.4 months' median follow-up, the risk of recurrence is reduced by 27% (HR 0.73, P = .0001) and the mortality reduced by 17% (HR 0.83, P = .08).[38] More secondary malignancies were reported in the tamoxifen group (53 vs 27); endometrial cancers comprised 11 of these cancers in the tamoxifen group and 5 in the exemestane group.[37]

Overall, exemestane was well tolerated ( Table 9 ).[37] Although preclinical data suggested that exemestane has bone-protective activity,[39] an increase in the incidence of osteoporosis was observed in patients who switched to exemestane (7.4% vs 5.7% in the tamoxifen-only arm; P = .05). The observed safety profiles in ICCG 96, and in another placebo-controlled safety trial,[40] indicate that this steroidal drug is associated with a loss in bone mineral density. Tamoxifen was more frequently associated with gynecologic symptoms and thromboembolic disease and exemestane more frequently associated with arthralgia. Furthermore, some of the toxicities associated with exemestane, such as diarrhea and visual disturbances, were not previously reported in adjuvant trials of the nonsteroidal aromatase inhibitors.

A QOL study was conducted in 582 patients observed for 2 years after randomization. According to a FACT-B scale and an endocrine subscale, no significant differences were observed between the groups treated with tamoxifen and exemestane. Some endocrine-related symptoms improved during the period (hot flushes, night sweats, gynecologic and sexual problems), whereas some endocrine-related symptoms (decreased libido, vaginal dryness) persisted.[41]

ITA -- Italian Tamoxifen Arimidex Trial

Study Design. This open-label trial was designed to compare the effects of 5 years of tamoxifen with 2 to 3 years of tamoxifen followed by anastrozole (1 mg/d) for 5 years.[42,43] Patients (n = 448) were postmenopausal women with ER+ and node-positive disease. Approximately 45% had prior adjuvant chemotherapy. Important limitations of this trial included the small size, open-label design, and changes in inclusion criteria. Inclusion criteria for the sequential arm of the trial specified that patients would receive 2 to no more than 3 years of tamoxifen; however, the switch to anastrozole took place at highly variable time points (median 28 months; range, 20 to 40 months).

Results. At the 36-month median follow-up visit, the sequential arm had fewer total events (regional or distant recurrences, or new contralateral breast primary cancers) than the tamoxifen-only arm. The risk of recurrence was significantly lower (HR 0.36; P = .006) in the sequential arm compared with the tamoxifen-only arm.[43]

Patients in the sequential treatment group had more gastrointestinal symptoms and a higher incidence of hypercholesterolemia, but fewer gynecologic symptoms, than patients in the tamoxifen-only group. Serious adverse events were reported in 14 patients in the sequential arm and in 29 patients in the tamoxifen-only arm.[43]

ARNO -- Arimidex-Nolvadex

Study Design. This is a phase 3 trial of 5 years of tamoxifen vs sequential tamoxifen for 2 years followed by 3 years of anastrozole, conducted by the Austrian Breast Cancer Study Group in collaboration with the German Adjuvant Breast Cancer Group.[6] The two study groups differ somewhat in their implementation of the trial design. Thus the Austrian Group randomized the patients upfront whereas the German Group randomized the patients within 2 years after surgery. The trial was begun in 1996 and has recruited approximately 3200 postmenopausal women with hormone-sensitive breast cancer. The primary end point is recurrence-free survival (RFS), defined as time from randomization to locoregionally or distant recurrence or to a new contralateral breast cancer. Secondary end points include distant RFS and tolerability.

Results. The mean age of enrolled patients was 63 years; 27% of patients had node-positive tumors, and all tumors were hormone receptor-positive. No patients had received chemotherapy.[44] With 28 months' median follow-up, 143 events had been reported. For RFS with anastrozole versus tamoxifen, the HR was 0.59 (P < .0018).[44] Further data presentation must await peer-reviewed publication of final results.

BIG 1-98 (Sequential Arms)

In the early sequential adjuvant therapy arms of this 4-arm trial (which also includes 2 monotherapy arms), patients receive either 2 years of letrozole therapy followed by 3 years of tamoxifen therapy (n = 1530) or 2 years of tamoxifen therapy followed by 3 years of letrozole therapy (n = 1530) (Figure 2). The primary end point is DFS.

Results. Initial results are not yet available.

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