HER3, p95HER2, and HER2 protein expression levels define multiple subtypes of HER2-positive metastatic breast cancer

Abstract

Trastuzumab is effective in the treatment of HER2/neu over-expressing breast cancer, but not all patients benefit from it. In vitro data suggest a role for HER3 in the initiation of signaling activity involving the AKT–mTOR pathway leading to trastuzumab insensitivity. We sought to investigate the potential of HER3 alone and in the context of p95HER2 (p95), a trastuzumab resistance marker, as biomarkers of trastuzumab escape. Using the VeraTag® assay platform, we developed a dual antibody proximity-based assay for the precise quantitation of HER3 total protein (H3T) from formalin-fixed paraffin-embedded (FFPE) breast tumors. We then measured H3T in 89 patients with metastatic breast cancer treated with trastuzumab-based therapy, and correlated the results with progression-free survival and overall survival using Kaplan–Meier and decision tree analyses that also included HER2 total (H2T) and p95 expression levels. Within the sub-population of patients that over-expressed HER2, high levels of HER3 and/or p95 protein expression were significantly associated with poor clinical outcomes on trastuzumab-based therapy. Based on quantitative H3T, p95, and H2T measurements, multiple subtypes of HER2-positive breast cancer were identified that differ in their outcome following trastuzumab therapy. These data suggest that HER3 and p95 are informative biomarkers of clinical outcomes on trastuzumab therapy, and that multiple subtypes of HER2-positive breast cancer may be defined by quantitative measurements of H3T, p95, and H2T.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-013-2665-0) contains supplementary material, which is available to authorized users.

CD38 expression and complement inhibitors affect response and resistance to daratumumab therapy in myeloma

“…Several other clinical studies have also shown that efficacy of monoclonal antibodies including rituximab, 37,38 alemtuzumab, 39 and trastuzumab 40,41 is partly dependent on target antigen expression. Importantly, it is unlikely that CD38 is a general prognostic factor in MM.…”

Role of HER2-Related Biomarkers (HER2, p95HER2, HER3, PTEN, and PIK3CA) in the Efficacy of Lapatinib plus Capecitabine in HER2-Positive Advanced Breast Cancer Refractory to Trastuzumab

“…The VeraTag reporter is conjugated to an antibody (anti-HER3 Mouse mAb Ab-6; Labvision, Fremont, CA, USA) that binds a distinct epitope of HER3, while biotin is conjugated to a second antibody (anti-HER3 Mouse mAb clone B9A11; Monogram Biosciences) that recognizes a different HER3 epitope [13]. …”

“…HER2-positive breast cancer subtypes may be defined by quantitative measurements of total HER3 (H3T), p95HER2 (p95), and total HER2 (H2T) [13]. Multiple analyses of the HER family pathway were performed in formalin-fixed, paraffin-embedded tissues using VeraTag technology.…”

Non-HER2 signaling pathways activated in resistance to anti-HER2 therapy in breast cancer

“…Influence of HER3 expression on PFS has been shown to be especially relevant in HER2-positive MBC patients treated with trastuzumab, with a HR of 5.8 (p = 0.001) [12,35], but also in non-metastatic BC it has demonstrated a reduced PFS at 10 years (75.5 vs. 64.8 %; p = 0.001) in a cohort of 449 patients [14,36]. On the contrary, higher HER3 mRNA expression has been associated with better PFS in 740 MBC HER2-positive patients treated with trastuzumab plus docetaxel and/or pertuzumab (HR: 0.81; p = 0.0348) [15,16,37] (Tables 3, 4).…”