Abstract P3-08-03: Breast cancer index and prognostic performance in invasive lobular breast cancer
Authors: Sella Tal , Nunes Raquel , Treuner Kai , Atkinson Jennifer , Wong Jenna , Zhang Yi , Exman Pedro , Dabbs David , Richardson Andrea , Schnabel Catherine , Sgroi Dennis , Oesterreich Steffi , Cimino-Mathews Ashley , Metzger Otto 
Published: March 2020

Abstract
Background: Invasive lobular carcinoma (ILC) has distinct clinical, histologic, molecular, and biological characteristics. Dyscohesive cells infiltrating the mammary stroma, lack of E-cadherin expression, mutations in the PIK3CA pathway and lower incidence of GATA3 mutations are hallmarks of these tumors. As a result of these molecular features, tumor biology is of key importance in determining prognosis and treatment approaches for ILC. The Breast Cancer Index (BCI) is a gene expression signature validated as a significant and independent prognostic factor both for risk of overall (0-10 years) and late (5-10 years post-diagnosis) distant recurrence, and is predictive of extended endocrine benefit in patients with early-stage, HR+ breast cancer. The objective of the current study is to examine BCI prognostic risk stratification and potential clinical utility specifically in ILC. Methods: In this multi-institutional, prospectively defined retrospective study, FFPE tumor samples from 356 HR+ stage I-III N0 and N+ ILC patients diagnosed between 1997-2011 were collected. Genomic risk stratification was performed using BCI-prognostic models (N0: gene expression alone; N+: gene expression plus tumor size and grade) using previously validated assay cut-points. Prognostic performance for 10-year and late DR risk was estimated using Kaplan-Meier analysis and the difference was evaluated by log-rank test and Cox proportional hazards regression. Results: Results were generated on 311 evaluable patients (99% ER+, T1 52%, 42% N+, 66% grade II) with 10 years of median follow-up. BCI significantly stratified ILC patients into three prognostic risk groups based on 10-year risk of DR (p &lt; 0.0001). Notably, BCI low and intermediate risk patients demonstrated similar patterns and rates of distant recurrence, with limited risk in early DR (0-5 years) and increasing risk of late DR (5-10 years), constituting a single risk group in lobular cancer. Analysis combining the low and intermediate risk groups resulted in 53% and 47% of patients classified as BCI low/int and high risk, respectively. In well and moderately differentiated N0 tumors, 18% of patients were classified by BCI as high risk. The overall 10-year risk of DR was significantly different (hazard ratio [HR] =4.67, 95% confidence interval [CI]: 2.24 - 9.74; p &lt; 0.0001) between BCI low/int (6.9%, 95% CI: 2.4% - 11.2%) and high (27.9%, 95% CI: 19.3% - 35.5%). The risk was also significantly different for both early (0-5 years; p = 0.001) and late DR (5-10 years; p = 0.02). For early DR, the risk was 1.4% (0.0% - 3.3%) and 11.8 (6.2% - 17.1%) for the low/int and high risk groups, respectively; while for late DR, the risk was 5.6% (1.4% - 9.5%) and 18.2% (10.1% - 25.6%), respectively. Conclusion: BCI was a significant prognostic factor in risk stratification of ILC and identified a substantial proportion of ILC, which is generally associated with indolent characteristics, that were associated with a high 10-year risk of DR and late DR. In addition, BCI reclassified a considerable proportion of clinically low and moderate grade tumors as high genomic risk. These results support a role for genomic classification with BCI to define distinct prognostic subtypes based on tumor biology towards more individualized treatment strategies for patients with ILC.
Citation Format: Tal Sella, Raquel Nunes, Kai Treuner, Jennifer Atkinson, Jenna Wong, Yi Zhang, Pedro Exman, David Dabbs, Andrea Richardson, Catherine Schnabel, Dennis Sgroi, Steffi Oesterreich, Ashley Cimino-Mathews, Otto Metzger. Breast cancer index and prognostic performance in invasive lobular breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-03.