Introduction Predictive biomarkers (BMs) for OGA would optimise treatment selection and avoid ineffective therapy. Metabolic response (MR) defined as >35% decrease in tumour FDG Standardised Uptake Value (SUV) between day 0 and day 14 after starting chemotherapy has a high negative predictive value (95%) for response, but limited positive predictive value (50%). Combining molecular BMs and serum cell death markers with FDG-PET may optimise response prediction. We used global gene expression profiling (GEP) and cell death ELISAs to identify molecular BMs and serum markers that when combined with FDG-PET would improve predictive accuracy.
Methods 28 patients with locally advanced/metastatic OGA received platinum based chemotherapy (PBC). FDG-PET scans were at day 0 & 14 and GEP (Affymetrix ST1.0 Exon Genechips) on day 0 tumour biopsies. A tissue microarray comprising an independent set of 154 OGA who had surgery +/-neoadjuvant PBC was used with immunohistochemistry (IHC) for qualification of GEP results. Cytokeratin 18 (CK18) M30 (apoptosis) and M65 (apoptosis+necrosis) ELISAs (Pevivia, Sweden) were used to assess cell death from serial serum samples during chemo. Radiological response was assessed after 3/4 cycles of PBC by RECISTv1.1.
Results We identified a gene expression signature (86 genes) that separated FDG-PET MR patients (>35% fall SUV day 0–14) into those that do and do not have a RECIST response. In cross validation this signature correctly predicted response in 14/14 metabolic responders (MRs). Pathway analysis on GEP data identified potential novel mechanisms of response including the Leptin pathway. Leptin mRNA was higher in FDG MRs who did not have a RECIST response compared to those that did (p=0.026). In the independent set high Leptin protein by IHC was associated with lack of histopathologic response to neoadjuvant PBC (n=64, p=0.007). High Leptin expression also had a therapy independent prognostic effect with longer survival in the absence of histopathologic response or with no neoadjuvant PBC and in low Leptin patients poor survival was mitigated to a degree by neoadjuvant PBC. Serum CK18M30 decreased from day 0–14 in MRs but in metabolic non-responders (MNRs) there was a smaller fall or a rise (p=0.021). Levels in MNRs did not change with subsequent chemo. In MRs levels continued to fall in RECIST responders but increased again in non-responders.
Conclusion Molecular biomarkers (Leptin in particular) and serum cell death markers combine with FDG-PET to optimise response prediction in OGA. Further investigation of this combined molecular, serum and imaging approach is warranted.
Competing interests None declared.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.