Abstract P5-05-04: Myc as a poor prognostic marker for ER+ inflammatory breast cancer (IBC): Quantitative estrogen receptor (ER) expression analysis and gene expression analysis in ER+ IBC vs non-IBC
Authors: Iwase T , Harano K , Masuda H , Kida K , Espinosa Fernandez JR , Hess KR , Wang Y , Woodward WA , Layman RM , Dirix L , Van Laere SJ , Bertucci F , Ueno NT 
Published: May 2019

Background

Estrogen receptor-positive (ER+) primary inflammatory breast cancer (IBC) has a poorer prognosis than ER+ primary non-IBC. Our objective was to determine the association between ER positivity and survival outcome in order to elucidate the biological reason that ER+ IBC is more aggressive than non-IBC.

Methods

We retrospectively determined the relationship between ER expression by immunohistochemistry staining and neoadjuvant chemotherapy response as well as survival outcome for 189 patients with ER+ and HER2-negative (HER2-) IBC and 896 case-matched patients with stage III non-IBC seen at MD Anderson Cancer Center between January 1989 and April 2015. We performed gene expression (GE) analysis for 39 patients with ER+/HER2- IBC and 40 patients with non-IBC to detect genes that are specifically overexpressed in IBC. Logistic regression and Cox proportional hazards model were used to determine the predictive and prognostic value of percentages of cells positive for ER and progesterone receptor (PR) among the patients with ER+/HER2- IBC and non-IBC. Recursive partitioning analysis (RPA) was used to determine the optimal cutoff points for ER% and progesterone receptor (PR) % that maximized differences in survival. The identified cutoff points were tested in an external cohort of 192 ER+/HER2- IBC patients from Institut Paoli-Calmettes in France.

Results

The median values for ER% for IBC and non-IBC were 85 (range, 1-100) and 90 (range, 1-100), respectively. The logistic regression model demonstrated a lack of a relationship of ER% with pathological complete response rate to neoadjuvant chemotherapy both in IBC (P=0.29) and non-IBC (P=0.14). Expression of ER was significantly associated with distant disease-free survival (DDFS); hazard ratio (HR), 0.56 [95% CI, 0.37-0.83] per 50% increase in ER%; P&lt;0.05). Also, ER% was significantly associated with overall survival (OS) (HR, 0.40 [95% CI, 0.25-0.63] per 50% increase in ER%; P&lt;0.05). RPA showed that 91.5% and 9.0% were the optimal cutoff points for ER% and PR%, respectively, for DDFS and overall survival in IBC patients. However, the cutoff points could not be validated in the French external cohort. In the GE study, 84 genes were detected as significantly distinguishing ER+ IBC from non-IBC. Among the top 15 canonical pathways shown by IPA, the ERK/MAPK signaling pathway, PDGF pathway, insulin receptor signaling pathway, and IL-7 signaling pathway were associated with the ER signaling pathway. MYC upregulation was observed in three of these four pathways. Indeed, ER+/HER- IBC had significantly higher MYC amplification compared to those with non-IBC (P&lt;0.05) and higher MYC level was associated with poor relapse free survival for IBC (HR, 1.85 [95% CI, 1.05-2.70], P&lt;0.05).

Conclusions

Increased ER positivity was significantly associated with improved survival in ER+/HER- IBC patients. ER+/HER- IBC had several activated pathways with MYC upregulation compared to non-IBC. MYC upregulation was associated with a poor survival outcome for ER+/HER- IBC. The results indicate that MYC is a key gene for understanding the aggressive biological behavior of ER+/HER- IBC.

Citation Format: Iwase T, Harano K, Masuda H, Kida K, Espinosa Fernandez JR, Hess KR, Wang Y, Woodward WA, Layman RM, Dirix L, Van Laere SJ, Bertucci F, Ueno NT. Myc as a poor prognostic marker for ER+ inflammatory breast cancer (IBC): Quantitative estrogen receptor (ER) expression analysis and gene expression analysis in ER+ IBC vs non-IBC [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-05-04.