E. Strong (ed.). Gastric cancer. Principles and practice. Springer (2015)
The clinical efficacy of anti-HER therapies is dependent on the level of HER2 expression in both breast and gastric cancers. Currently, the two approved techniques to evaluate HER2 expression include IHC and FISH. However, as discussed previously in this chapter, the HER2 expression of esophagogastric cancers can be heterogenous and show incomplete staining on IHC. Furthermore, in breast cancers, it has been shown that HER2 expression can be discordant between the primary lesion and distant metastatic disease, and may also vary between metastatic lesions [60–63].
The development of radiolabeled antibodies is an active area of research. Position emission tomography (PET) imaging of HER2 with radiolabeled trastuzumab may allow PET imaging to quantitate HER2 expression levels and guide therapy selection and allow for monitoring of response. Such a technology would allow for noninvasive assessment of HER2 expression in the primary tumor and all sites of metastases simultaneously, a clear potential advantage over single site biopsies. Furthermore, the biodistribution of trastuzumab can vary in each patient and is heavily impacted by the extent of tumor load, which may contribute to variations in patient responses [64, 65]. Use of functional imaging technology may thus help elucidate the molecular basis of resistance to trastuzumab. Studies have evaluated trastuzumab radiolabeled with Indium-111 (111In), Copper-64 (64Cu) in xenograft cancer models.
Zirconium-89 (89Zr) is an attractive radionuclide for use in functional PET imaging due to its favorable characteristics, with a half-life of 78 h, and shown to be stable with respect to ligand disassociation in human serum for greater than 7 days. The first in-human 89Zr-trastuzumab PET imaging study showed excellent tumor uptake and visualization of HER2-positive breast metastases, including in-brain tumor lesions . Xenograft studies performed by researchers at Memorial Sloan Kettering Cancer Center (MSKCC) have demonstrated that 89Zr-trastuzumab PET is highly specific for HER2-positive gastric tumors, whereas as 18-FDG and 18-FLT PET were unable to differentiate HER2-positive from HER2 negative tumors (Fig. 5.1) 89Zr-trastuzumab PET is now being evaluated by this group in humans with HER2-positive esophagogastric cancers .
Fig. 5.1. Specificity of 89Zr-trastuzumab for HER2-positive tumors. Coronal 89Zr-trastuzumab, 18F-FDG, and 18FFLT PET images of athymic nude mice bearing subcutaneous HER2-positive NCI-N87 (left) and HER2-negative MKN-74 (right) tumors are shown. +ve = positive; -ve = negative. This research was originally published in JNM. (Janjigian YY, Viola-Villegas N, Holland JP, et al. ; images on the right: © by the Society of Nuclear Medicine and Molecular Imaging, Inc.)
Individual esophagogastric cancer subtypes have heterogenous tumor characteristics and clinic outcomes, making this malignancy a complex disease to treat. Cell culture lines and even mouse xenografts of human tumor cell lines have had variable predictive power in the translation of cancer therapies into clinical setting . These models often fail to reproduce the complexities of the tumor microenvironment and the interaction between the tumor cells and the immune system, which are integral components to tumor proliferation and metastasis .
Tumor graft models or patient-derived xenografts (PDXs) are being studied as an alternative, more clinically predictive model of human malignancies. PDXs are based on the transfer of primary tumors directly from the patient into an immunodeficient mouse. The tumors can be implanted either heterotopically or orthotopically. Heterotopic PDX model involves implanting tumors into the subcutaneous tissue of the mouse. Orthotopic models involve direct implantation of the tumor into a specific mouse organ. The heterotopic method allows for easier cell transfer and precise monitoring of tumor growth. The orthotopic models, while more technically challenging, are considered to more accurately mimic the human tumors . Limitations of using PDX models for research include the higher cost and more specialized maintenance compared to cultured cell lines. Furthermore, PDX models can require long latency periods after engraftment and variable engraftment rates between 23 and 75% depending on the tumor type [69, 71].
Fig. 5.2. MSKCC Patient-Derived Xenograft (PDX) Program Schema: esophagogastric cancer models implemented to bring targeted agents to the clinic
PDX models are actively being studied in esophagogastric cancers. Janjigian and colleagues at MSKCC have established both heterotopic and orthotopic PDX models using nonobese diabetic/ severe combined immunodeficient (NOD/SCID) mouse (Fig. 5.2). The established PDXs include HER2-positive trastuzumab refractory models, MET+ models, and signet ring gastric model with germ line CDH1 mutation. Tumor engraftment rates of 46% for orthotopic tumors and 26% for heterotopic implants were reported . PDX models are a promising platform to further validate differences in tumor biology and guide the design of clinical trials. Further, molecular profiling and therapeutic experiments with the PDX models are underway to identify distinct molecular signatures predictive of response to these agents.
Next generation sequencing (NGS) has allowed for cheaper and faster sequencing compared to traditional Sanger sequencing. The Cancer Genome Atlas (TCGA) is an ongoing research program supported by the National Cancer Institute and National Human Genome Research Institute at the National Institutes of Health. The TCGA researchers will identify the genomic changes in more than 20 different types of human cancer, including gastric and esophageal cancers. The genomic sequencing data will be available to the research community and allow for a more comprehensive understanding of the acquired genetic, genomic, and epigenetic alterations in cancer cells that can be translated into clinical and therapeutic advances.
The integrated esophagogastric TCGA data provide insight in the tumorigenesis of gastric cancers and identify further targetable mutations, beyond HER2. Whole exome and genome sequencing of esophageal adenocarcinoma tumors and normal pairs identified 26 significantly mutated genes. The sequencing identified novel mutated genes not previously implicated in this disease, including mutations in chromatin modifying factors and candidate contributors: SPG20, TLR4, ELMO1, and DOCK2 . The esophagogastric TCGA identified four distinct subsets of the disease: (1) Epstein Barr Virus (EBV) tumors with marked methylation, PIK3CA mutations, PD-L1/2 amplification, (2) Tumors with Microsatellite instability (MSI) and frequent activating mutations, (3) chromosomally instable (CIN) tumors with frequent oncogenic amplifications, and (4) chromosomally stable/diffuse type tumors with novel mutations of RHOA (ras homolog gene family, member A). RHOA encodes a small guanosine-5′-triphosphatase (GTPase) that displays potent oncogenic activity when overexpressed. Recent TCGA sequencing data on diffuse-type gastric carcinoma revealed newly identified recurrent RHOA hotspot mutations in diffuse-type gastric cancers, which were not seen in intestinal-type tumors [74, 75]. The presence of RHOA mutations was associated with tumors located in the cardia, poorer tumor differentiation, and less likely to be associated with TP53 mutations. Further detailed mechanistic and translational studies are ongoing .
At Memorial Sloan Kettering Cancer Center, NGS using the integrated mutation profiling of actionable cancer targets (IMPACT) assay is being performed to identify previously unrecognized biomarkers of drug sensitivity and resistance. The IMPACT assay is capable of identifying point mutations, small insertion/deletion events (indels), and large gene level and intragenic copy number aberrations in 275 cancer-associated genes. In the ongoing phase II study of afatinib in metastatic HER2-positive, trastuzumab refractory cancer, preand posttreatment biopsies are being collected in all patients, allowing for a unique opportunity to define the prevalence of p95-HER2 and other genetic aberrations that have been associated with trastuzumab resistance in preclinical models .
Genomic sequencing technology will allow for the comprehensive profiling of tumor specimens and holds the potential to guide cancer treatment. Efforts are ongoing at institutions worldwide to correlate the genetic and molecular information of the genomic sequencing data with clinical data to guide individualized therapies and diagnostic tools.
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