Background

Combination of letrozole and lapatinib improved progression-free survival (PFS) compared with letrozole and placebo in patients with hormone receptor-positive (HR+)/HER2+ metastatic breast cancer (MBC), but not HR+/HER2-negative (HER2-) disease (JCO 2009). However, HR+ disease is clinically and biologically heterogeneous with all intrinsic molecular subtypes (Luminal A, Luminal B, HER2-enriched [HER2E] and Basal-like) identified. Here, we tested retrospectively the prognostic and predictive ability of intrinsic subtype in tumor samples of the EGF30008 trial.

Methods

Expression profiling from FFPE tumor tissues was performed on the nCounter platform. Tumors were classified into each intrinsic subtype using the research-based PAM50 classifier (JCO 2009). Cox proportional hazard models for PFS and overall survival (OS) were used to generate point estimates of hazard ratios (HR) and corresponding 95% confidence intervals (CIs). Changes in likelihood ratio χ2 values were used to measure and compare the relative amount of information of each variable. Variables evaluated were: age, prior endocrine therapy, presence of visceral disease, number of metastatic sites, performance status, clinical HER2 status, and treatment. To determine whether the intrinsic subtypes were predictive of lapatinib benefit, we tested the interaction term of subtype by treatment arm in a Cox model that also included the main effects. Kaplan-Meier plots were used to depict the proportion of patients free from progression as a function of time.

Results

Tumor samples from 821 patients (63.8%) were profiled (85.7% primary and 14.3% metastatic tumor samples). Clinical-pathological features of this patient subset were well balanced compared with the original set. Within the entire cohort, all subtypes were identified: Luminal A (46.5%); Luminal B (29.7%); HER2E (7.4%); Basal-like (3.4%) and normal-like (12.9%). Within HER2+ disease, 28.6% of samples were HER2E. Intrinsic subtype was found the strongest prognostic factor independently associated with PFS and OS in all patients, and in patientswith HER2-negative or HER2+ disease (P<0.0001). Median PFS and OS for each subtype within clinically HER2-negative disease were: Luminal A (16.85 and 45.0 months), Luminal B (10.97 and 37.0 months), HER2E (4.67 and 16.0 months) and Basal-like (4.14 and 23.0 months). Within clinically HER2-negative disease (n=644), 16 patients (2.5%) had HER2E disease. Patients with HER2-/HER2E disease benefited from lapatinib (6.5 vs 2.6 months; PFS HR =0.24, 95% CI: 0.07-0.86; P=0.019; HER2E vs not treatment interaction P=0.016). Finally, intrinsic subtype was not predictive of benefit from lapatinib within HER2+ disease.

Conclusions

HR-positive disease is biologically heterogeneous and intrinsic subtypes are strongly prognostic in a first-line MBC setting. HR+/HER2- disease with a HER2E profile may benefit from lapatinib. The clinical value of intrinsic subtyping in HR+ MBC warrants further investigation, but patients with Luminal A/HER2-negative MBC disease might be good candidates for letrozole monotherapy in the first-line setting regardless of visceral disease and number of metastases.

Citation Format: Prat A, Cheang MCU, Galván P, Nuciforo P, Paré L, Adamo B, Viladot M, Press MF, Gagnon R, Ellis C, Johnston S. Prognostic and predictive abilities of intrinsic subtype in hormone receptor-positive metastatic breast cancer from the EGF30008 phase III clinical trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-08-16.