A poor prognosis ER and HER2-negative, nonbasal, breast cancer subtype identified through postneoadjuvant endocrine therapy tumor profiling

Abstract

502 Background: Tumor estrogen receptor (ER) loss after neoadjuvant endocrine therapy (NET) was recently identified as an independent prognostic marker relapse (relative risk relapse 2.8 CI 1.2–6.4 P=0.02 and death from breast cancer RR 7.0 CI 2.4–20.9 P=0.0005 - SABCS 2007 Abstract 62). To investigate the switch from ER+ to ER- after NET we examined microarray gene expression data accrued from a multicenter Phase 2 study of neoadjuvant letrozole. Methods: Agilent 44K whole genome array data was generated from tumor specimens with >50% tumor prior to therapy (BL), and on treatment (OT) samples one month and/or surgery. 65 BL and OT pairs or triplets were obtained and a simple clustering algorithm was used to examine relationships between the BL and OT samples and reference samples (14 Basal [BAS] 6 HER2+ [HER2] and 4 Normal Breast). 50 genes were applied that have been identified as a minimal set capable of giving an intrinsic breast cancer subtype classification. Results: The BL clustering and central ER analysis revealed three false hormone receptor positive tumors, two ER- HER2- tumors that clustered with BAS cluster and one ER- HER2- tumor that strongly expressed the proliferation cluster (PLN) but not BAS or LUM markers. The OT clustering experiment revealed an additional 8 tumors in the ER- cluster that had HER2- /BAS-/LUM-/PLN+ characteristics with markedly poor Ki67 response (P=0.015). In BL samples these tumors were originally ER IHC+ and appeared in the LUM branch. These observations support the initial observation that about 10% of ER+ tumors transition to an ER- state early after the initiation of endocrine treatment (ET). Of the eight relapses that have occurred in the phase II letrozole trial population to date, three were tumors in the post treatment HER2-/BAS-/LUM-/PLN+ cluster and two were in the BL false ER+ group. Conclusions: Tumors that lose ER with neoadjuvant endocrine treatment lack both BAS and LUM gene expression. These unclassified proliferative tumors can exhibit a fulminant clinical course. ER expression should be tested soon after initiating NET (one month) to identify early ER loss so that treatment approaches can be adjusted to reflect the highly aggressive and ET resistant nature of this newly defined tumor subtype. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration University Genomics