Abstract P2-10-10: Clinical implications of molecular heterogeneity in highly proliferative, ER-positive, HER2-negative breast cancer
Authors: Bianchini G , Pusztai L , Kelly CM , Iwamoto T , Callari M , Symmans WF , Gianni L 
Published: August 2014

Abstract
Objectives: Different clinical behaviors are observed in tamoxifen-treated and untreated ER-positive, HER2-negative highly-proliferative breast cancer (BC) that demonstrate either high (highERS) or low (lowERS) expression of estrogen-related genes (Bianchini SABCS 2011). LowERS tumors are intrinsically endocrine resistant and at significant risk of relapse in the first 5 yrs after diagnosis. We studied lowERS and highERS BC in pts treated with neoadjuvant chemotherapy (NAC) and examined prognostic and predictive markers in the highest risk group of lowERS BC.
Methods: We examined affymetrix gene expression data from 193 ER+/HER2−, high proliferation BC from pts treated with taxane-anthracycline-based NAC followed by endrocrine therapy. Previously defined cut-offs for markers of proliferation (MKS), and estrogen-related genes were applied (Bianchini SABCS 2011). Within the lowERS group, we examined pts treated with no systemic adjuvant therapy (n = 137; 50 events); adjuvant tamoxifen-only (n = 141; 36 events); and NAC (n = 127, 27 RCB0/I). We performed gene enrichment analysis for 2617 gene sets with known biological function (by 5000 random permutations). Primary endpoints were distant event free survival (DEFS) with follow-up censored at 5-yrs and pathological response (pathR) using the residual cancer burden (RCB) (Symmans JCO 2007).
Results: The median follow-up of the NAC series was 3.1yrs. The DEFS at 4yrs was 0.94 [0.87–1.00] and 0.70 [0.60–0.81] in the high and low ERS groups, respectively (p = 0.004) (despite the higher rate of pathR (RCB0/I) to NAC in the low ERS group (9.5% and 21.9%; p = 0.04)). The pathR was prognostic in the lowERS group [HR 9.1 (CI 1.23–67.4); p = 0.009] but not in highERS (p = 0.485). In contrast, a different outcome was observed in BC with RCBII-III, were the 4-yrs DEFS was 0.93 [0.86–1.00] and 0.61 [0.49–0.76] in high and low ERS group, respectively (p = 0.0007). In the lowERS group there was substantial overlap in biological functions associated with prognosis in both tamoxifen-treated and untreated pts. At a conservative threshold of p &lt; 0.0005, 38 gene sets were significant (31 good-prognosis involved in adaptive immune function, inflammation and chemotaxis and 7 poor prognosis gene sets involved in regulation of nuclear division and cell polarity). Only proliferation-related gene sets were predictive of RCB0/I. MKS as a continuous variable was predictive of pathR beyond clinical variables [OR 5.43 (2.04–16.1); p = 0.001].
Conclusions: Among ER+/HER2−, high proliferation BC the highERS group showed a low pathR rate with excellent prognosis even if there was residual disease. The lowERS group showed a higher rate of pathR which was significantly prognostic for good outcome. Lack of pathR in this group predicted for very poor prognosis despite subsequent adjuvant endocrine treatment. The clinical behaviour and aggressiveness of this subgroup is similar to triple negative tumors. The prognostic relevance of immune function provides a rationale for testing immunotherapeutic strategies in this subgroup.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-10.