Changes in the Dynamic Relationship between ER and HER2 in Paired Breast Cancer (BC) Biopsies from Patients (Pts) with Recurrent Tamoxifen-Resistant Breast Cancer.

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Abstract Background: Paired biopsies at diagnosis and relapse on tamoxifen (TAM) provide information regarding adaptive changes associated with endocrine resistance. We previously reported that conversion to a HER2+ phenotype occurs infrequently1, however modest increases in HER2 may be relevant in the context of TAM resistance. Also while TAM resistance in general is associated with a fall in mean ER and PgR levels, this masks changes in individual pts.Aim: To determine whether a subset of HER2 negative BC demonstrated modest increases in HER2 by IHC and FISH, and if so whether this correlated with changes in ER and PgR expression in individual pts.Methods: Triplicate TMAs were constructed of paired primary and recurrent tumor samples from pts relapsing after adjuvant TAM. TMAs were stained for ER and HER2, whole sections for PgR. HER2 amplification was assessed by FISH.Results: Paired samples from primary and TAM-resistant recurrences were available on 53 ER+ and/or PgR+ pts. 10% had a HER2+ primary (IHC3+ and FISH+). 19% (10/53) showed increasing HER2 in the relapsed tumor (0 to 1+ in 5 pts, 1+ to 2+ in 2 pts and 0/1+ to 3+ in 3 pts). The 3 pts converting to 3+ also became FISH+. 71% (38/53) had stable or decreasing HER2. DFI was 50.3 months in the subset with stable or decreasing HER2, 40.2 in the subset with increasing HER2, and 35.2 in the HER2+ subset (p=NS). We next compared changes in ER and PgR in the 3 subsets. Among pts with stable or decreasing HER2 (N=38), there was a significant decrease in mean H-scores for both ER (p=0.001) and PgR (p=0.002) at relapse (Fig 1); the majority recurred with reduced ER (76%) or PgR levels (84%). In contrast, among pts with increasing HER2, there was no change in mean ER or PgR levels (Fig 2A); however when considering changes in individual pts, there was a balanced split between tumors relapsing with up- vs. down-regulation in ER/PgR (Fig 2B,C). In the HER2 positive subset, 100% of the pts relapsed with suppressed ER and PgR.Conclusion: In an updated series of TAM-resistant pts, we show that while conversions to HER2 3+/FISH+ remain rare (5%), modest increases in HER2 are more frequent (19%). TAM resistance in general is associated with decreasing ER and PgR. However, among pts with adaptive increases in HER2, TAM resistance is associated with either down- or up-regulation in ER expression and function. This is consistent with data from acquired endocrine resistance models we previously reported2,3.1Gutierrez et al, JCO 20052Pancholi et al, ERC 2008,3 Martin et al, JBC 2003 Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 704.