cs1rugo_dec10 | prIME Oncology

Updates from Major Endocrine Therapy Trials Confirm Efficacy of Aromatase Inhibitors

December 13, 2009—During the 2009 San Antonio Breast Cancer Symposium in San Antonio, updated data were presented from several major trials examining hormone therapy in the early and extended adjuvant settings.

Long term follow-up of the Intergroup Exemestane Study
Judith Bliss, MSc (The Institute of Cancer Research, Sutton, United Kingdom), presented data from a 91 month median follow-up of the Intergroup Exemestane Study (IES), an investigator-led study in postmenopausal women with ER-positive/unknown primary breast cancer that has already demonstrated significant, clinically important benefits from switching adjuvant endocrine therapy after 2-3 years tamoxifen to exemestane (Coombs RC, et al. Lancet. 2007;369:559-570). The current exploratory analyses, including 4052 patients with ER-positive tumors (ER+) and 547 patients with ER-unknown tumors, focused on breast cancer–free survival (BCFS), site of distant recurrence, and incidence of non-breast second primary cancers.

The following results were obtained from this study:

Overall BCFS favored exemestane in patients with ER+ and ER-unknown tumors
- Unadjusted hazard ratio (HR) of 0.81 (95%CI: 0.71, 0.92); P = .001
Distant recurrence including bone was greater in patients treated with tamoxifen
Treatment with exemestane resulted in a lower number of reported non-breast second primary cancers
Breast cancer outcomes (overall survival and disease-free survival) remained improved with exemestane at 9 years

These data confirm that the protective effect of switching to exemestane, compared to continuing on tamoxifen, on relapse rate is maintained for at least 5 years post-treatment completion in women who were disease free after 2-3 years of tamoxifen. In addition, treatment with exemestane resulted in a modest but persistent improvement in overall survival.

Cancer Res. 2009;69(Suppl): Abstract 12.

Outcomes of premenopausal women at diagnosis in MA17
Paul Goss, MD, PhD (Dana-Farber Cancer Institute, Boston, United States), presented data on the outcomes of women who were premenopausal at the diagnosis of early-stage breast cancer in the NCIC CTG MA.17 trial. MA.17 previously demonstrated that adjuvant letrozole after 5 years of tamoxifen markedly reduced the risk of recurrence in women with ER+ early-stage breast cancer and improved overall survival in women presenting with node-positive disease. The current analysis included premenopausal (n = 889) postmenopausal (n = 4227) patients.

The following results were obtained from this study:

Both premenopausal and postmenopausal women at diagnosis of breast cancer derived benefit from letrozole, though women who were premenopausal at diagnosis had significantly greater benefit with letrozole treatment in terms of disease-free survival than those with postmenopausal status
- Premenopausal: HR = 0.25, 95% CI: 0.12-0.51; P <.0001
- Postmenopausal: HR = 0.69 with 95% CI from 0.52 to 0.91; P = .0008
Distant disease-free survival and overall survival were more pronounced in premenopausal women

Reported treatment-related toxicities in premenopausal women were infrequent, though premenopausal women reported a higher impact of treatment on quality of life. In addition, data from this analysis reported that premenopausal women with ER+ breast cancer benefit significantly from extended letrozole therapy after they become menopausal. This benefit was similar in women who delayed endocrine therapy up to 6 years after receiving treatment with tamoxifen. The authors state that women who are premenopausal at the time of diagnosis but become postmenopausal anytime before, or during, adjuvant tamoxifen should be considered for extended adjuvant therapy with letrozole.

Cancer Res. 2009;69(Suppl): Abstract 13.

Adjusting for selective crossover in BIG 1-98
Meredith Regan, ScD (Dana-Farber Cancer Institute, Boston, United States), presented data from an updated analysis of the BIG 1-98 trial, which is a double-blind randomized trial comparing 5 years of letrozole, 5 years of tamoxifen, and sequences of letrozole and tamoxifen as adjuvant therapy for postmenopausal women with endocrine-responsive breast cancer. Previous results of BIG 1-98 demonstrated that letrozole significantly improved disease-free survival; in addition, a trend for improved overall survival was seen in the intent-to-treat (ITT) population, and was significant in the artificially censored analysis. The goal of the current analysis was to estimate the true magnitude of the treatment effect of letrozole:tamoxifen if patients randomized to tamoxifen did not selectively cross over to letrozole. Inverse probability of censor weighting (IPCW), a well-established and published statistical method, weights the follow-up for the women who stay on tamoxifen so that they account not only for themselves, but also for the censored follow up of matched patients who cross over. Results from this analysis demonstrated that the IPCW estimate of treatment effect (HR = 0.84) for disease-free survival with letrozole was larger than the ITT and artificially-censored estimates, and the IPCW estimate (HR = 0.83) with letrozole for overall survival was larger than the ITT estimate but suggested the artificially-censored estimate overestimated the overall survival treatment effect. The IPCW estimate (HR = 0.81) with letrozole for time to distant recurrence was identical to the censored analysis, which was larger than the ITT estimate. These updated results from BIG 1-98 confirm the statistically significant (P <.05) overall survival benefit for 5 years of letrozole compared with 5 years of tamoxifen.

Cancer Res. 2009;69(Suppl): Abstract 16.

Rheumatologic evaluation of letrozole
Side effects such as arthralgia and/or myalgia (A/M) occur in 20% to 35% of women on aromatase inhibitor therapy with onset as early as 1-2 months from treatment initiation; in addition, as many as 20% of patients may discontinue therapy due to A/M. Denise Yardley, MD (Sarah Cannon Research Institute, Nashville, United States), presented data from a study assessing the tolerability of letrozole in postmenopausal women with HR+ early breast cancer who discontinued anastrozole due to grade 2-3 A/M. Results from this study demonstrated that approximately 10% of patients discontinued letrozole therapy due to ≥ grade 2 A/M. Indeed, these patients experienced significantly less A/M and improved QoL compared with baseline. At the end of the 6 month follow-up period, 87% of patients continued on therapy with letrozole, which is similar to the rate that was observed in the ATOLL study (Briot K, et al. Presented at the 2008 San Antonio Breast Cancer Symposium, San Antonio, Texas, December 10-14, 2008. Abstract 1142).

Cancer Res. 2009;69(Suppl): Abstract 805.