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Young-onset Rectal Cancer: Unique Tumoral Microbiome and Correlation with Response to Neoadjuvant Therapy
Michael White*1, Ashish Damania2, Jumanah Y. Alshenaifi3, Pranoti Sahasrabhojane2, Oliver Peacock1, Brian Bednarski1, Jillian Losh2, Matthew C. Wong2, Zuzana Berkova3, Sa Nguyen1, Neal Bhutiani4, George Chang1, Jennifer A. Wargo4, Nadim Ajami2, Scott Kopetz3, Y. Nancy You1
1Colon and Rectal Surgery, University of Texas MD Anderson Cancer, Houston, TX; 2Platform for Innovative Microbiome and Translational research, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX; 3Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX; 4Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX

Introduction: Nearly one in four cases of rectal cancer is now diagnosed in young adults under age 50, and the majority are regionally or distantly metastatic at presentation. Patients with young-onset rectal cancer (YORC) often face arduous treatments and uncertain long-term outlooks. We aimed to elucidate the microbiome in YORC, given reported associations among external exposures, the host, and the microbiome in oncology. We hypothesized that tumoral microbiomes may reflect unique correlative and potentially causative factors in YORC.

Materials & Methods: Patients with YO- (<50 years old) or later-onset rectal cancer (LORC, ≥50 years old) were prospectively enrolled and had tumors and tumor-adjacent normal tissues (TANs) collected via endoscopic biopsy prior to therapy. After whole genome sequencing, metagenomic analysis was performed using MetaPhlAn3 for taxonomical classification. Association of microbial signatures were examined comparing tumors vs. TANs, and tumors of YO- vs. LORCs. Response to neoadjuvant therapy was categorized as major pathological response (MPR, ≤10% residual viable tumor) vs. non-MPR and microbial signatures were examined for response correlation (defined as 20% global prevalence and FDR<0.05).

Results: Among 108 rectal cancers, 37 (34%) were YO- and 71 (66%) LORC. 108 tumor and 76 TANs were analyzed. We identified and recapitulated bacteria known as commonly associated with rectal cancer including, Parvimonas micra (p=8.39E-07), Fusobacterium nucleate (p=3.31E-06), Clostridium symbiosum (p=1.72E-05), and Bacteroides thetaiotamicron (p=0.029) known for colonization resistant during inflammation. For both YO and LORC, tumor microbiome signatures were distinct from TANs. YORC tumor microbiome was dominated by Escherichia coli (p<0.001), P. micra (p<0.001), and C. symbiosum (p<0.001), while LORC tumors were dominated by F. nucleatum (p=0.014), P. micra (p=0.014), and C. symbiosum (p< 0.001). MPR was observed in 47 (44%) patients, with complete pathologic response (ypT0N0M0) in 14 (13%). MPR in YORC was associated with Eggerthella lenta (p<0.001),Bacteroides dorei (p<0.001), and Dorea formicigenerans (p<0.001); in contrast, MPR in LORC was associated with Roseburia intestinalis (p<0.001). Network analysis of non-MPR tumors vs. paired TAN tissues demonstrated a preponderance of oral bacteria which was not observed in MPR tumors.

Conclusion: The tumoral bacterial signatures were distinct for YORC when compared with LO. Signatures associated with response to neoadjuvant therapy differed among YO- and LORCs. These early findings warrant further analyses to decipher correlative versus mechanistic associations, buy hint at the potential to utilize microbial modulation tools to augment standard of care treatment regimens.

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