Synapse - Genomic stratification beyond Ras/B-Raf in colorectal liver metastasis patients treated with hepatic arterial infusion

Genomic stratification beyond Ras/B-Raf in colorectal liver metastasis patients treated with hepatic arterial infusion Journal Article

Authors:	Smith, J. J.; Chatila, W. K.; Sanchez-Vega, F.; Datta, J.; Connell, L. C.; Szeglin, B. C.; Basunia, A.; Boucher, T. M.; Hauser, H.; Wasserman, I.; Wu, C.; Cercek, A.; Hechtman, J. F.; Madden, C.; Jarnagin, W. R.; Garcia-Aguilar, J.; D'Angelica, M. I.; Yaeger, R.; Schultz, N.; Kemeny, N. E.
Article Title:	Genomic stratification beyond Ras/B-Raf in colorectal liver metastasis patients treated with hepatic arterial infusion
Abstract:	Background: Resection of colorectal liver metastases (CLM) can cure disease, but many patients with extensive disease cannot be fully resected and others recur following surgery. Hepatic arterial infusion (HAI) chemotherapy can convert extensive liver disease to a resectable state or decrease recurrence risk, but response varies and no biomarkers currently exist to identify patients most likely to benefit. Methods: We performed a retrospective cohort study of CLM patients receiving HAI chemotherapy whose tumors underwent MSK-IMPACT sequencing. The frequency of oncogenic alterations and their association with overall survival (OS) and objective response rate were analyzed at the individual gene and signaling pathway levels. Results: Three hundred and seventy patients met inclusion criteria: 189 (51.1%) who underwent colorectal liver metastasectomy followed by HAI + systemic therapy (Adjuvant cohort), and 181 (48.9%) with unresectable CLM (Metastatic cohort) who received HAI + systemic therapy, consisting of 63 (34.8%) with extrahepatic disease and 118 (65.2%) with liver-restricted disease. Genomic alterations were similar in each cohort, and no individual gene or pathway was significantly associated with objective response. Patients in the adjuvant cohort with concurrent Ras/B-Raf alteration and SMAD4 inactivation had worse prognosis while in the metastatic cohort patients with co-alteration of Ras/B-Raf and TP53 had worse OS. Similar findings were observed in a validation cohort. Conclusions: Concurrently altered Ras/B-Raf and SMAD4 mutations were associated with worse survival in resectable patients, while concurrent Ras/B-Raf and TP53 alterations were associated with worse survival in unresectable patients. The mutual exclusivity of Ras/B-Raf, SMAD4, and TP53 may have prognostic value for CLM patients receiving HAI. © 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
Keywords:	signal transduction; adult; cancer chemotherapy; aged; gene mutation; major clinical study; overall survival; sequence analysis; systemic therapy; adjuvant therapy; antineoplastic agent; colorectal cancer; gene; metastasis; cohort analysis; validation study; retrospective study; liver; intraarterial drug administration; genomics; gene inactivation; inoperable cancer; floxuridine; hepatic arterial infusion; metastasis resection; tp53 gene; cancer prognosis; colorectal liver metastasis; human; male; female; priority journal; article; smad gene; implantable infusion pumps; ras b raf gene
Journal Title:	Cancer Medicine
Volume:	8
Issue:	15
ISSN:	2045-7634
Publisher:	Wiley Blackwell
Date Published:	2019-11-01
Start Page:	6538
End Page:	6548
Language:	English
DOI:	10.1002/cam4.2415
PUBMED:	31503397
PROVIDER:	scopus
PMCID:	PMC6825986
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85072199869&doi=10.1002%2fcam4.2415&partnerID=40&md5=bda192253b90f255d8589ff27f56277e
Notes:	Article -- Export Date: 2 December 2019 -- Source: Scopus