PAST
Despite curative hepatectomy for patients with colorectal cancer liver metastases (CRLM), most will recur in either the liver, the extrahepatic environment, or both.1 Adjuvant hepatic artery infusion (HAI) chemotherapy mitigates intrahepatic recurrence;2 however, some patients recur despite both curative-intent hepatectomy and adjuvant HAI plus systemic therapies. We hypothesized that genomic profiling of resected tumors may inform such recurrence patterns and highlight biologic underpinnings that could enable surgical selection and/or oncologic decision making. As such, recent reports from our group have identified genomic profiles that correlate with response to HAI chemotherapy, ensuing conversion to resection, and prolonged overall survival in patients with initially unresectable CRLM.3 Therefore, we sought to interrogate genomic drivers of intrahepatic and extrahepatic recurrence patterns following curative hepatectomy and adjuvant HAI plus systemic chemotherapy.4
PRESENT
Following curative-intent hepatectomy and HAI with systemic chemotherapy, alterations in FLT3, KRAS, and SMAD4 genes as well as in the RTK-RAS, RAS/RAF, and cell cycle pathways were associated with extrahepatic recurrence. No discrete alterations in genes or the signaling pathways were significantly associated with liver-specific or overall recurrence. Notably, RAS/RAF-TP53 co-alteration was the only genomic signature associated with worse overall, intrahepatic, and extrahepatic recurrence-free survival at 3 years. Of note, no specific alterations were associated with overall, intrahepatic, or extrahepatic recurrence for patients managed with curative-intent hepatectomy followed by adjuvant systemic chemotherapy only. Taken together, although genomic profiles of resected CRLM in this study were similar to those reported in other studies, RAS/RAF-TP53 co-alteration was the only predictor of liver recurrence despite curative resection as well as local and systemic chemotherapy.
FUTURE
This report highlights the novel association between liver recurrence and RAF/RAS-TP53 cooperativity. Given that cooperativity between these foundational oncogenic driver alterations has been previously associated with dis-proportionate innate immune cell enrichment and T-cell exclusion in diverse gastrointestinal cancers, our data might suggest an intersection between the genomic architecture in resected CRLM, the hepatic immune microenvironment, and intrahepatic recurrence.5 Further codification of this relationship and its biologic basis is necessary to identify novel therapeutic strategies to mitigate recurrence in patients with RAF/RAS-TP53 co-altered tumors.
Footnotes
DISCLOSURES Raja R. Narayan, Jashodeep Datta, and Michael I. D’Angelica declare they have no conflicts of interest.
REFERENCES
- 1.D’Angelica M, Kornprat P, Gonen M, et al. Effect on outcome of recurrence patterns after hepatectomy for colorectal metastases. Ann Surg Oncol. 2011;18(4):1096–103. [DOI] [PubMed] [Google Scholar]
- 2.Kemeny NE, Chou JF, Boucher TM, et al. Updated long-term survival for patients with metastatic colorectal cancer treated with liver resection followed by hepatic arterial infusion and systemic chemotherapy. J Surg Oncol. 2016;113(5):477–84. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Datta J, Narayan RR, Goldman DA, et al. Distinct genomic profiles are associated with conversion to resection and survival in patients with initially unresectable colorectal liver metastases treated with systemic and hepatic artery chemotherapy. Ann Surg. 2020. 10.1097/SLA.0000000000004613. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Narayan RR, Datta J, Goldman DA, et al. Genomic predictors of recurrence patterns after complete resection of colorectal liver metastases and adjuvant hepatic artery infusion chemotherapy. Ann Surg Oncol. 2022. 10.1245/s10434-022-12085-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Dosch AR, Chatila WK, Ban Y, et al. Ras-p53 genomic cooperativity as a model to investigate mechanisms of innate immune regulation in gastrointestinal cancers. Oncotarget. 2021;12(20):2104–10. [DOI] [PMC free article] [PubMed] [Google Scholar]