Abstract A03: Association of Fusobacterium nucleatum (F. nucleatum) with progression-free survival (PFS) and overall survival (OS) with 2nd-line FOLFIRI +/- regorafenib in metastatic colorectal cancer (mCRC)
Authors: Lee Michael S. , Keku Temitope O. , McCoy Amber , Selitsky Sara R. , Parker Joel , Auman Todd , Hammond Kelli , Patil Sushant A. , Manyam Ganiraju , Kopetz Scott , Sanoff Hanna K. , Innocenti Federico 
Published: December 2020

Abstract
Background: F. nucleatum is an oral anaerobe aberrantly found in up to 43% of CRCs. F. nucleatum presence is associated with additional known prognostic variables, including BRAF mutation and immune infiltration. In nonmetastatic CRC, F. nucleatum is associated with post-chemotherapy recurrence and inferior cancer-specific survival. However, the prognostic value of F. nucleatum in mCRC is not well described. We evaluated the association between F. nucleatum, integrated with other significant prognostic clinicopathologic factors, in a prospective clinical trial cohort of mCRC.
Methods: LCCC1029 was a 2:1 randomized phase II trial of 2nd-line chemotherapy with 5-fluorouracil/irinotecan plus either regorafenib or placebo in mCRC. DNA and RNA were extracted from FFPE archival tumor samples, and quantitative PCR to measure F. nucleatum levels was successfully performed on 73 of those samples. We compared PFS and OS using Kaplan-Meier method and log-rank tests, and univariate and multivariate hazard ratios (HR) were estimated using Cox proportional hazards method.
Results: Among the 73 mCRC patients with F. nucleatum quantitated, 20 (27%) had a high level and 53 (73%) had undetectable or low levels of F. nucleatum. On univariate analysis, F. nucleatum high level was not associated with PFS (HR 0.78, 95% CI 0.46-1.33; log-rank p=0.36) or OS (HR 0.83, 95% CI 0.46-1.51; log-rank p=0.54). However, the F. nucleatum positive subgroup trended toward higher rates of BRAF mutation (12%, vs 2% in F. nucleatum low/negative), KRAS/NRAS mutation (47% vs 27%), and MSI-High (12% vs 5%). We thus performed multivariate analyses of PFS and OS including F. nucleatum high level, BRAF mutation, KRAS/NRAS mutation, MSI, prior antiangiogenic therapy, and age on the subgroup of 58 patients who had results from all platforms. On multivariate analysis, high F. nucleatum expression trended toward association with improved PFS, with HR 0.57 (0.30-1.10, p=0.095). BRAF mutation, prior antiangiogenic therapy, and F. nucleatum were significantly associated with improved OS, with high F. nucleatum expression having adjusted HR 0.48 (0.23-0.99, p=0.048).
Conclusions: Expression of F. nucleatum in the tumor of patients with mCRC was significantly associated with improved OS in mCRC. While results need to be validated, these findings suggest that F. nucleatum is associated with prognosis in a context-dependent fashion and may confer differential prognosis in nonmetastatic versus metastatic CRC patients.
Citation Format: Michael S. Lee, Temitope O. Keku, Amber McCoy, Sara R. Selitsky, Joel Parker, Todd Auman, Kelli Hammond, Sushant A. Patil, Ganiraju Manyam, Scott Kopetz, Hanna K. Sanoff, Federico Innocenti. Association of Fusobacterium nucleatum (F. nucleatum) with progression-free survival (PFS) and overall survival (OS) with 2nd-line FOLFIRI +/- regorafenib in metastatic colorectal cancer (mCRC) [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr A03.