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. 2019 Oct 15;25(20):6170-6179.
doi: 10.1158/1078-0432.CCR-19-0318. Epub 2019 Jul 29.

Intratumoral Fusobacterium Nucleatum Levels Predict Therapeutic Response to Neoadjuvant Chemotherapy in Esophageal Squamous Cell Carcinoma

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Free PMC article

Intratumoral Fusobacterium Nucleatum Levels Predict Therapeutic Response to Neoadjuvant Chemotherapy in Esophageal Squamous Cell Carcinoma

Kensuke Yamamura et al. Clin Cancer Res. .
Free PMC article

Abstract

Purpose: Emerging evidence indicates that gut microbiome plays a crucial role in the cancer pathogenesis. Although Fusobacterium nucleatum (F. nucleatum) is associated with poor prognosis in multiple cancers, its clinical significance in predicting response to chemotherapy in patients with esophageal squamous cell carcinoma (ESCC) remains unclear.

Experimental design: The F. nucleatum levels were quantified by qPCR assays in tumor tissues from 551 patients with ESCC from two independent cohorts, including 101 patients who received neoadjuvant chemotherapy prior to curative resection. Associations between F. nucleatum burden and recurrence-free survival (RFS), as well with chemotherapeutic response were evaluated using response evaluation criteria in solid tumors (RECISTs), primary tumor metabolic response defined by maximum standardized uptake value (SUVmax) changes in positron emission tomography-CT (PET/CT), and pathologic tumor regression grade (TRG).

Results: High burden of F. nucleatum in patients with ESCC associated with poor RFS in both training [log-rank P = 0.02; HR = 1.61; P = 0.03] and validation cohorts (log-rank P = 0.003; HR = 1.96; P = 0.004). Importantly, patients with ESCC with high levels of F. nucleatum displayed poor chemotherapeutic response for all three evaluation methods: RECIST (P = 0.04), SUVmax change in PET/CT (P = 0.0004), and TRG (P = 0.003).

Conclusions: We conclude that high levels of intratumoral F. nucleatum have a prognostic significance for predicting poor RFS in patients with ESCC. More importantly, our data indicates that higher F. nucleatum burden correlates with poor response to neoadjuvant chemotherapy, suggesting the possibility that an antibiotic intervention against this bacterium may significantly improve therapeutic response in patients with ESCC.

Conflict of interest statement

Conflicts of interest: None of the authors has any potential conflicts to disclose.

Figures

Figure 1:
Figure 1:. F. nucleatum expression in patients with ESCC.
(A) The expression of F. nucleatum in 45 pairs of ESCC and adjacent normal tissue in the training cohort, and (B) in 48 pairs of the validation cohort. (C) The relative amount of F. nucleatum in 207 ESCC tissue according to T category in training cohort, and (D) in 344 ESCC tissue in validation cohort. *p<0.05; **p<0.01, ***p<0.001
Figure 2:
Figure 2:. High intratumoral F. nucleatum is associated with worse prognosis in ESCC.
Comparison of F. nucleatum expression levels in patients with or without recurrence in (A) the training and (B) the validation cohort. Kaplan-Meier analysis of RFS for ESCC patients with high (red) or low (blue) F. nucleatum levels in (C) the training and (D) the validation cohort. Kaplan-Meier analysis of RFS for ESCC patients with low F. nucleatum levels in T1 (blue) or T2–4 tumor (pink), or high F. nucleatum levels in T1 (red) or T2–4 tumor (green) in (E) the training and (F) the validation cohort. Fn indicates Fusobacterium nucleatum. *p<0.05
Figure 3:
Figure 3:. Intratumoral F. nucleatum levels are associated with chemotherapeutic response.
Chemotherapeutic response and the rate of responders in the validation cohort by comparing F. nucleatum high (red) and low (blue) patients using RECIST (A and B), PET/CT (C and D) and TRG (E and F). RECIST, response evaluation criteria in solid tumors. PET/CT, Positron Emission Tomography - Computed Tomography. TRG, Tumor Regression Grade. *p<0.05; **p<0.01, ***p<0.001

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