HER2 heterogeneity as a biomarker in cancer

A method for HER-2 directed therapy comprising

• (a) assessing HER2 heterogeneity in a tumor, comprising
• (i) contacting a sample of the tumor with a biomarker-specific reagent that specifically binds to HER2 protein and detecting HER2 protein in the sample,
• (ii) contacting the sample of the tumor with a first nucleic acid probe that specifically binds HER2 genomic DNA, and detecting HER2 gene amplification status in the sample,
• (iii) contacting the sample of the tumor with a second nucleic acid probe that specifically binds HER2 RNA, and detecting HER2 RNA status in the sample,
• wherein the sample is a surgical tissue sample,
• wherein the tumor is a solid tumor,
• wherein the tumor is gastric cancer,
• (b) scoring the HER2 protein (IHC), HER2 gene (DISH), and HER2 RNA (RNA-ISH),
• wherein scoring is categorized as:
• Group A for samples exhibiting IHC 3+ and DISH+, and RNA-ISH+,
• Group B for samples exhibiting IHC 3+ and DISH−, and RNA-ISH−,
• Group C for samples exhibiting IHC 2+ and DISH+, RNA-ISH+,
• Group D for samples exhibiting IHC 2+ and DISH−, RNA-ISH−,
• Group E for samples exhibiting IHC 1+ and DISH+, RNA-ISH+,
• Group F for samples exhibiting IHC 1+ and DISH−, RNA-ISH−,
• Group G for samples exhibiting IHC 0 and DISH+, RNA-ISH+, and
• Group H for samples exhibiting IHC 0 and DISH−, RNA-ISH−,
• (c) predicting that the tumor is responsive to the HER2-directed therapy if the tumor reveals a first foci having a first score selected from Group A to Group G and a second foci having a second score selected from Group A to Group G, wherein the first score and the second score are not the same, and
• (d) when the first score and the second score are indicative of a tumor being responsive to HER2-directed therapy, administering HER-2 directed therapy selected from the group consisting of trastuzumab, trastuzumab emtansine, pertuzumab, neratinib, and lapatinib.