High Baseline TNF-α Levels may Associate with Poor Outcomes after Total Neoadjuvant Therapy for Gastroesophageal Cancer: Initial Biomarker Analysis from a Prospective Study

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<h3>Purpose/Objective(s)</h3> We previously reported the feasibility and early efficacy of neoadjuvant FOLFIRINOX followed by CRT for gastric and gastroesophageal junction (GEJ) adenocarcinoma. However, response to neoadjuvant therapies in these cancers is heterogenous and response biomarkers are needed. We previously identified candidate blood inflammatory and angiogenesis biomarkers in gastric and GEJ adenocarcinoma patients. Here, we investigated circulating inflammatory and angiogenesis cytokines as biomarkers of response to neoadjuvant chemoradiation. <h3>Materials/Methods</h3> We enrolled patients on an NCI-sponsored, prospective, single arm study (NCT03279237). Key eligibility criteria included: histologically confirmed T3/4 or lymph node (LN) positive gastric or GEJ adenocarcinoma, and ECOG PS ≤1. Extensive LN disease beyond the surgical field (supraclavicular or para-aortic) was permitted if deemed able to be encompassed within the radiotherapy field. Patients received neoadjuvant FOLFIRINOX x 8 cycles, restaging, CRT (45 Gy for gastric, 50.4 Gy for GEJ) with concurrent C/T, restaging, followed by surgical resection. We collected blood samples at baseline and at pre-defined time-points during chemoradiation, including C1D1, C1D8, restaging, and at time of disease progression. For this analysis, we measured baseline levels of proinflammatory markers, including IFN-ɣ, IL-10, IL-12p70, IL-4, IL-6, IL-8, and TNF-α; growth factors and soluble receptors including bFGF, sFLT1, PlGF, VEGF-A, VEGF-C, VEGF-D; HGF, TGF-β, and Ang-2. Baseline biomarker levels were correlated with clinical endpoints: pathologic complete response (pCR) and progression-free survival (PFS). Given the exploratory nature of this analysis, p≤0.10 was considered statistically significant. <h3>Results</h3> From October 2017 to June 2018, 25 pts were enrolled, with baseline assays available on 24 pts. With a median follow up of 43.1 months (range: 36.6-50.2), there were 7 patients who had a pCR, 11 patients with disease progression, and 11 patients who have died. In our initial exploratory analysis, none of the candidate biomarkers was different between patients who showed a pCR after chemoradiation versus those who did not (p-value: range 0.28-1.00). However, we found that a plasma TNF-α level above median was associated with worse PFS rates at 12 months (42% versus 83%) and at 24 months (33% versus 75%) (n=12, p=0.06). <h3>Conclusion</h3> Prior studies have suggested associations between inflammation biomarkers and outcomes. Among patients with gastroesophageal adenocarcinoma treated with total neoadjuvant therapy, higher baseline of circulating TNF-α may be associated with worse PFS. Further exploration of TNF-a as a biomarker or therapeutic target in model systems may be warranted to further understand our observations.