In the treatment of postmenopausal estrogen receptor–positive women with lobular carcinoma, letrozole appears to have a greater benefit than tamoxifen, according to an analysis of this subset of patients in the Breast International Group (BIG) 1-98 trial reported at the 35th Annual San Antonio Breast Cancer Symposium.¹

“The magnitude of benefit of adjuvant letrozole varies by histology and estrogen receptor subgroup,” said Otto Metzger-Filho, MD, of Dana-Farber Cancer Institute in Boston. “Letrozole is associated with statistically significant reductions in disease-free and overall survival events for both lobular and ductal carcinoma, but the magnitude of benefit is higher for patients diagnosed with lobular carcinoma.” In both histologic subtypes, patients with luminal B tumors derived more benefit than those with luminal A, he added.

Study Background

BIG 1-98 was a randomized phase III study comparing 5 years of tamoxifen monotherapy, letrozole monotherapy, and two sequential treatments (tamoxifen followed by letrozole, or letrozole followed by tamoxifen) in postmenopausal women with hormone receptor–positive early breast cancer. The current analysis focused on patients randomly assigned to the monotherapy arms of BIG 1-98 study and included patients who had centrally reviewed pathology data for histologic subtypes, hormone receptors, HER2, and Ki67.

Lobular and ductal tumors centrally classified as hormone receptor–positive and HER2-negative were further subdivided into luminal A (low proliferative) or luminal B (high proliferative) subsets using a Ki67 cutoff of 14%. In the ductal carcinoma subset (n = 2,599), 45% of women were luminal A and 56% were luminal B, while in the lobular carcinoma group (n = 324), these proportions were 73% and 27%, respectively.

Disease-free and overall survival rates were estimated using a method called inverse probability of censoring weighted analysis, which provided a better estimate of treatment benefit than intent-to-treat analysis due to the high selective crossover rate (25%) from tamoxifen to letrozole after the study results were presented in 2005, he said.

Summary of Results

At 8.4 years of median follow-up, patients with lobular carcinoma experienced a 52% reduction in the hazard of a disease-free survival event in favor of letrozole, whereas patients with ductal carcinoma experienced a 20% reduction. The observed difference was significantly related to histology (interaction P value = .03). For overall survival, the magnitude of benefit of letrozole compared to tamoxifen was again higher in the subset with lobular disease than in the ductal subset, and significantly related to histology (interaction P value = .045). At 8 years, survival rates were 88% and 84% for lobular patients treated with letrozole and tamoxifen, respectively.

In the multivariate analysis of disease-free survival correcting for classic clinicopathologic factors, significant interactions were observed between treatment and histology (ductal/lobular, interaction P value = .006) and treatment and subtype (luminal A/luminal B, interaction P value = .01), Dr Metzger reported. All hazard ratios favored letrozole, but the hazard ratio of 0.33 for lobular luminal B tumors was most striking, he added. Hazard ratios for other tumor subtypes were 0.49 for lobular luminal A tumors, 0.64 for ductal luminal B tumors, and 0.95 for ductal luminal A tumors. ■

Disclosure: Dr. Metzger-Filho reported no potential conflicts of interest.

Reference

1. Metzger O, Giobbie-Hurder A, Mallon E, et al: Relative effectiveness of letrozole compared with tamoxifen for patients with lobular carcinoma in the BIG 1-98 trial. 2012 San Antonio Breast Cancer Symposium. Abstract S1-1. Presented December 5, 2010.