PMC6691136_01
ERBB2 expression detected by immunohistochemistry (A) in original patient tumor (top) and PDX 712 tumor (bottom). Visualization of Chromosome 17 region containing the ERBB2 amplicon (B), the number of ERRB2 copies are shown in original patient tumor (blue) and PDX tumors F0 (purple) and F1 (pink). Computed tomography (CT) images of the patient's thorax (C) before T-DM1 treatment (left panel), at the time of treatment response (middle panel), and progression (right panel).
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F1
HER-2 status was positive by immunohistochemistry (IHC) and copy number analysis using Cytoscan HD (Figures 1A,B). The patient completed 3 cycles of treatment and a CT scan in early May 2017 demonstrated treatment response and the patient reported complete disappearance of coughing symptoms and felt more ease at breathing (Figure 1C). T-DM1 was interrupted for 3 weeks to confirm that the imaging was indeed demonstrating tumor and not infection in the lung and treatment resumed in July 2017. The patient was maintained on T-DM1 with no reported side-effects until disease progression in September 2017 (Figure 1C) and he passed away from CNS disease in January of 2018. Adenocarcinoma was confirmed by histology in the PDX tumor and HER-2 amplification was confirmed by copy number analysis and IHC and matched the original patient tumor (Figures 1A,B).
Response to treatment in PDX models. PDX drug efficacy of Trastuzumab and T-DM1 in two consecutive studies performed on NOG mice engrafted with F0 PDX tumor (A,B) and with Trastuzumab resistant PDX tumor from mouse 712 (F1) (C,D). Data are presented as tumor volume (mm3) during treatment days (x axis). Each colored line represents a single mouse PDX.
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F2
Interestingly, of the 4 mice treated with Trastuzumab, only 1 demonstrated drug resistance while treatment with T-DM1 resulted in tumor regression in all mice tested (Figures 2A,B). Trastuzumab resistant PDX (mouse 712). This study showed emergence of resistance to Trastuzumab and validated the rapid and durable response to T-DM1 (Figures 2C,D).