PORTO-001 study: Changes in the oral microbiome and matrix metalloproteinases in patients with oropharyngeal squamous cell carcinoma undergoing definitive chemoradiotherapy.
Authors: Boavida Ferreira João , Subramanian Vasanth , Xiang Ye Y , Stone Simone , Xu Wei , Irish Jonathan Crawford , Cho John , Hosni Ali , Kim John , Wang Ben X , Coburn Bryan , Guimarães António , Spreafico Anna , Siu Lillian L. 
Published: June 2023

e18034

Background: Head and neck cancer patients treated with concurrent chemoradiotherapy (CRT) develop oral mucositis, with varying severity. However, knowledge about risk factors, biomarkers, treatment, and prognosis of oral mucositis is still limited. Methods: We designed an exploratory study to examine the changes in the oral microbiome and salivary and plasma levels of matrix metalloproteinases (MMP) in patients with locoregionally advanced oropharyngeal squamous cell carcinoma (OPSCC) undergoing definitive CRT. Patients were followed from screening to week 7 of treatment with CRT, which consisted of 70 Gy/35 fractions of radiation with cisplatin given at 100 mg/m2 q3weeks or weekly 40 mg/m2. Clinical and demographic data were collected at specified timepoints. Samples were collected at screening and on week 4 of treatment with CRT. A tumor swab was collected for microbiome analysis. Blood and saliva samples were collected for measurements of 7 MMPs and 26 other cytokines. The study population was summarized descriptively. The change in the cytokines and the α-diversity of microbiome data (week 4 vs screening) were examined using Wilcoxon signed rank test. Results: A total of 11 patients were included. Nine (82%) were male. 5 patients (45%) were stage III, and there were 2 patients (18%) for each of stages I, II, and IV. A history of smoking was present in 5 (45.4%) patients. p16 was positive in 9 (81.8%) patients. There was a median weight loss of 7.0% (5.1 kg) between screening and week 7 visits. Almost half (45%) of patients developed grade 2 oral mucositis. All patients developed radiation dermatitis, with most cases ranging between grades 2 and 3. There were no statistically significant changes in the salivary levels of cytokines. However, 1 patient developed clinical oral mucositis before all the other patients, at week 1, and this was associated with an upsurge in the salivary levels of IFN-γ, IL-6, TNF-α, MMP-1, MMP-2 and MMP-7. For all patients, there were statistically significant changes (median (95% confidence interval)) in the blood plasma levels of IP-10 (-0.1 fluorescence intensity (FI) (-0.3, -0.04), p = 0.01), MIP-1ß (0.2 FI (0.07, 0.5), p = 0.02), SDF-1α (1.4 pg/ml (0.07, 3.7), p = 0.02), MMP-1 (-0.4 pg/ml (-0.5, -0.09), p = 0.01), MMP-3 (0.4 pg/ml (0.03, 0.5), p = 0.02), and MMP-8 (-0.2 FI (-0.3, -0.02), p = 0.04). There was a 29.1% ((-3.0%, -32.8%), p = 0.005) reduction in α-diversity of microbiome at week 4 from screening. Conclusions: In this small series of patients diagnosed with OPSCC, there was a change in the plasma levels of IP-10, MIP-1ß, SDF-1α, MMP-1, MMP-3, and MMP-8, as well as a reduction in the α-diversity of the oral microbiome. Larger studies are needed to confirm these results. If confirmed, these changes might imply a potential role as predictive or pharmacodynamic biomarkers for oral mucositis.