Tumoral and circulating genomic landscape inform survival differences in colorectal carcinomatosis

Michael G White; Reed I Ayabe; Mohammad A Zeineddine; Fadl A Zeineddine; Abdelrahman M G Yousef; Mahmoud Yousef; Norman J Galbraith; J Bryan Iorgulescu; Christopher Scally; Keith Fournier; Timothy E Newhook; Nancy Y You; Jason Willis; Scott Kopetz; George J Chang; John Paul Shen; Abhineet Uppal

doi:10.1016/j.tranon.2025.102379

Tumoral and circulating genomic landscape inform survival differences in colorectal carcinomatosis

Transl Oncol. 2025 May:55:102379. doi: 10.1016/j.tranon.2025.102379. Epub 2025 Apr 3.

Authors

Michael G White¹, Reed I Ayabe², Mohammad A Zeineddine³, Fadl A Zeineddine³, Abdelrahman M G Yousef³, Mahmoud Yousef³, Norman J Galbraith¹, J Bryan Iorgulescu³, Christopher Scally⁴, Keith Fournier⁴, Timothy E Newhook⁴, Nancy Y You¹, Jason Willis³, Scott Kopetz³, George J Chang¹, John Paul Shen⁵, Abhineet Uppal⁶

Affiliations

¹ Department of Colon and Rectal Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
² Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Surgery, University of California Irvine Medical Center, Orange, CA, USA.
³ Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁴ Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁵ Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: JShen8@mdanderson.org.
⁶ Department of Colon and Rectal Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Now at Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA. Electronic address: abhineet.uppal@emory.edu.

Abstract

Colorectal peritoneal metastases (CPM) are the third most common site of metastatic spread of colorectal cancer and are associated with worse survival than other sites of metastatic disease. In recent years tumoral circulating tumoral DNA (ctDNA) mutational status has been increasingly utilized in clinical decision making for metastatic colorectal cancer patients despite its utility in CPM being poorly understood. Here we describe standard of care performed mutational profiles and associated outcomes for unresectable CPM patients, with a contextual comparison to 160 unresected colorectal liver metastases (CLM) patients. Of 508 patients, 288 (57 %) had CPM alone and 220 (43 %) had CPM with extraperitoneal metastases. Patients with synchronous CPM and CLM had worse overall survival (HR 1.67 [95 %CI 1.26-2.22]). Mutations in ctDNA were noted in 110/145 (75.9 %) of CPM patients, with mutations in KRAS or PIK3CA ctDNA being associated with worse survival. Importantly, the association between tumoral mutational profile and survival differed by site of metastatic disease. The prognostic significance of specific mutations, particularly BRAF and KRAS, differs between patients with CPM and CLM, and supports the distinct biology of these metastatic sites and the importance of tissue and circulating genomic profiling to risk-stratify these patients according to site of metastasis.

Keywords: BRAF mutation; Circulating tumoral DNA; Colorectal cancer; KRAS mutation; Liver metastasis; Peritoneal metastasis.