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

Abstract

Objective: To examine genomic correlates of conversion to resection (CTR and overall survival (OS) in patients with initially unresectable colorectal liver metastasis (IU-CRLM) treated with combination systemic and hepatic artery infusion (HAI) chemotherapy. Background: In patients presenting with IU-CRLM, combination systemic and HAI chemotherapy enables CTR with associated long-term OS in a subset of patients. Genomic correlates of CTR and OS in IU-CRLM have not been previously explored. Methods: Specimens from IU-CRLM patients receiving systemic/HAI chemotherapy (2003–2017) were submitted for next-generation sequencing. Fisher Exact test assessed associations with CTR, and Kaplan-Meier/Cox methods assessed associations with OS from HAI initiation. Results: Of 128 IU-CRLM patients, 51 (40%) underwent CTR at median 6 months (range: 3–35) from HAI initiation. CTR and persistently unresectable cohorts differed significantly in preoperative systemic chemotherapy exposure, node-positive primary status, and size of largest liver metastasis. Median and 5-year OS was 66 months and 51%. CTR was associated with prolonged survival (time-dependent HR 0.23,95% CI: 0.12–0.46, P < 0.001). The most frequently altered genes were APC (81%), TP53 (77%), and KRAS (37%). Oncogenic mutations in SOX9 and BRAF were associated with CTR. BRAF mutations, any RAS pathway alterations, and co-altered RAS/RAF-TP53 mutations were associated with worse survival. Classification and regression tree analysis defined prognostically relevant clusters of genomic risk to reveal co-altered RAS/RAF-TP53 as the highest risk subgroup. Co-altered RAS/RAF-TP53 remained independently associated with worse survival (HR 2.52, 95% CI: 1.37–4.64, P = 0.003) after controlling for CTR, number of liver metastases, and preoperative extrahepatic disease. Conclusions: Distinct genomic profiles are associated with CTR and survival in patients with IU-CRLM treated with HAI/systemic chemotherapy. Presence of SOX9, BRAF, and co-altered RAS/RAF-TP53 mutations are promising biomarkers that, when validated in larger datasets, may impact treatment of IU-CRLM patients.

Resectability, conversion, metastasectomy and outcome according to RAS and BRAF status for metastatic colorectal cancer in the prospective RAXO study

“…In a study that used hepatic arterial infusion for unresectable CRC liver metastases. Datta et al reported conversion rates of 45% in RAS and BRAF wt ± TP53 mt, 45% in RAS mt + TP53 wt, 39% in RAS mt + TP53 mt, and no conversions for BRAF mt patients [ 28 ]. Further, a conversion rate of 22% for RAS wt was observed in the FIRE-3 trial [ 29 ].…”

Management of Colorectal Cancer with Synchronous Liver Metastases: The Final Results of the Cosmic Inception Cohort Study

“…[26][27][28][29] The focus of much current controversy is on the management of patients with colorectal cancer and potentially resectable liver metastases -this is the cohort of the CoSMIC study. [30][31][32][33] Avoiding over-interpretation of these data, several points emerge. First, the study confirms that even in this selected referral population, those who do not or cannot undergo surgery, typically because of a combination of age, co-morbidity and tumor size have a less favourable outcome.…”

Distinct Mechanisms of Innate and Adaptive Immune Regulation Underlie Poor Oncologic Outcomes Associated with KRAS-TP53 Co-Alteration in Pancreatic Cancer

“…Leveraging this methodology, our group has focused on the genomic co-occurrence of KRAS and TP53 alterations as a prototype of this paradigm. Utilizing this extreme-outlier methodology, we have identified the association between KRAS-TP53 co-alteration and a clinical phenotype defined by chemoresistance [3], aggressive non-salvageable metastatic proclivity [4, 5], and worse cancer-related survival compared with KRAS or TP53 alterations alone [4] in non-PDAC GI cancers. Moreover, we and others have linked KRAS-TP53 co-alteration with the disproportionate enrichment of innate immune populations and immunoregulatory signaling in these GI cancers, implicating KRAS-TP53 cooperativity a model to investigate innate immune regulation [7].…”