Identification of a subpopulation of metastatic breast cancer patients with very high HER2 expression levels and possible resistance to trastuzumab

Abstract

1059 Background: Many HER2-positive patients with metastatic breast cancer (MBC) fail to respond to trastuzumab. We previously reported that precise quantitation of HER2 expression (H2T) by the HERmark assay identified a sub-population of IHC 3+, FISH(+) (positive) patients with low H2T levels that responded poorly to trastuzumab (Lipton, San Antonio Breast Cancer Symposium 2008, abs #32). Here we identify a sub-population of FISH(+) patients with very high H2T levels, that experience clinical outcomes that are indistinguishable from those of FISH(-) (negative) patients with low H2T levels. Methods: The HERmark assay was used to measure H2T in formalin-fixed, paraffin-embedded (FFPE) primary breast tumor specimens from 99 women treated with trastuzumab for MBC. Specimens were also tested by central FISH. A sub-population treatment effect pattern plot (STEPP) was generated to examine the progression-free survival (PFS) rate at 12 months after treatment with trastuzumab across the distribution of H2T. Kaplan-Meier (KM) analyses were performed comparing the PFS of FISH(-), H2T low (log10H2T < 1.25) patients with those of FISH(+), H2T high (log10H2T ≥ 1.95) and FISH(+), H2T intermediate (1.25 < log10H2T < 1.95) groups. Cutoffs were identified by lowest p-value in a positional scanning analysis. Results: The PFS rate improved gradually with increasing H2T in STEPP analyses. At the highest levels of H2T, an abrupt decrease in the PFS rate was observed, consistent with a reduction in susceptibility to trastuzumab. KM analyses demonstrated that patients who were FISH(+), H2T intermediate had a significantly longer PFS than patients who were FISH(-), H2T low (median PFS 12.6 vs. 4.5 mos; HR = 0.34; p < 0.0001). Patients that were FISH(+), H2T high experienced a PFS that was no better than patients that were FISH(-), H2T low (median PFS 4.6 vs. 4.5 mos; HR = 0.87; p = 0.68). Conclusions: Precise quantitation of HER2 expression levels allows the identification of multiple sub-populations of HER2(+) patients that have different clinical outcomes on trastuzumab. MBC patients with very high levels of H2T could represent a sub-group with de novo resistance to trastuzumab who may benefit from combined therapy. [Table: see text]