Abstract S1-1: Relative effectiveness of letrozole compared with tamoxifen for patients with lobular carcinoma in the BIG 1-98 trial.
Authors: Metzger O , Giobbie-Hurder A , Mallon E , Viale G , Winer E , Thürlimann B , Gelber RD , Colleoni M , Ejlertsen B , Bonnefoi H , Coates AS , Goldhirsch A , Gusterson B ,   BIG 1-98 Collaborative Group,   International Breast Cancer Study Group
Published: August 2014

Abstract
Background: Invasive lobular carcinoma (ILC) is mostly hormone receptor-positive (ER+) and associated with higher risk of late relapse (&gt; 5 years after diagnosis) when compared to invasive ductal carcinoma (IDC). In this analysis we investigate the magnitude of benefit of endocrine treatment (tamoxifen [tam] or letrozole [let]) and the patterns of relapse over time in patients with ILC (classical subtype) or IDC enrolled in the monotherapy arms of BIG 1-98 study (12-year update).
Material and methods: BIG 1-98 was a randomized, phase III study that compared five years of tam or let (monotherapy arms), or their sequences in post-menopausal women with ER+ early BC. There were 4922 patients enrolled in the monotherapy arms of BIG 1-98. This analysis includes patients who had centrally-reviewed histology data (n = 4080) and classified as IDC and ILC (n = 3660). Centrally-defined ER, PgR, Ki-67 were used to defined ER+ subtypes (n = 2923). ER+ subtypes were defined as Luminal A (ER+ and/or PR+ HER2− and Ki67&lt;14%) or Luminal B (ER+ and/or PR+, HER2− and Ki67≥14%) for both ILC and IDC. Follow-up in the tam arm was censored at the time of selective crossover for women who chose to switch to let.
Results: In the IDC subset, 1436 (44%) and 1163 (36%) were classified as Luminal A and Luminal B, while in the ILC subset 237 (59%) and 87 (22%) were classified as Luminal A and Luminal B, respectively. The 5-year DFS and OS estimates (±SE) for IDC and ILC are described in the table.

In multivariate models for DFS adjusted for classic clinicopathological features, significant interactions between treatment and histology (ILC or IDC), (p = 0.01) and treatment and subgroups (Luminal B or A), (p = 0.01) were observed. The DFS HRs for let vs tam were 0.51 (95% CI, 0.33 to 0.79) for ILC Luminal A and 0.35 (95% CI, 0.21 to 0.56) for ILC Luminal B. The DFS HRs for let vs tam were 0.93 (95% CI, 0.74 to 1.77) for IDC-Luminal A and 0.64 (95% CI, 0.52 to 0.78) and IDC-Luminal B. In the models for OS, the data suggest that the effect of letrozole varies by histology (interaction p = 0.053). The OS HRs for let vs tam was 0.39 (95% CI, 0.23 to 0.68) for ILC and 0.70 (95% CI, 0.57 to 0.86) for IDC. The hazards of DFS and OS events increased between 30 and 60 months after diagnosis among ILC pts treated with tam. In contrast, comparable hazard rates were observed for ILC pts treated with let and IDC pts treated with either let or tam.
Conclusions: The magnitude of benefit of adjuvant let varies by histology and ER-subgroup. Greater reduction in risk of a DFS event is noted in women with Luminal B for both IDC and ILC. There is a trend for OS favoring let in women with ILC. ILC pts treated with let have similar patterns of relapse over time when compared to IDC. The biologic underpinnings of these observations should be explored.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S1-1.