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 Journal Article
| Authors: | Datta, J.; Narayan, R. R.; Goldman, D. A.; Chatila, W. K.; Gonen, M.; Strong, J.; Balachandran, V. P.; Drebin, J. A.; Kingham, T. P.; Jarnagin, W. R.; Schultz, N.; Kemeny, N. E.; D'Angelica, M. I. |
| Article Title: | 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 wereassociated 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. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved. |
| Keywords: | genetics; liver neoplasms; antineoplastic agent; antineoplastic combined chemotherapy protocols; pathology; colorectal neoplasms; colorectal tumor; liver tumor; intraarterial drug administration; infusions, intra-arterial; genomics; hepatectomy; protein p21; proto-oncogene proteins p21(ras); b raf kinase; hepatic artery; proto-oncogene proteins b-raf; humans; human |
| Journal Title: | Annals of Surgery |
| Volume: | 276 |
| Issue: | 5 |
| ISSN: | 0003-4932 |
| Publisher: | Lippincott Williams & Wilkins |
| Date Published: | 2022-11-01 |
| Start Page: | e474 |
| End Page: | e482 |
| Language: | English |
| DOI: | 10.1097/sla.0000000000004613 |
| PUBMED: | 33214457 |
| PROVIDER: | scopus |
| PMCID: | PMC8502489 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 November 2022 -- Source: Scopus |
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