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Secondary resection of metastases is recommended in metastatic colorectal cancer (mCRC). Data describing changes in mutational profiles of corresponding primary tumor and metastatic tissue after conversion treatment are limited. Next generation sequencing was performed in formalin-fixed mCRC samples from patients of the FIRE-3 trial (FOLFIRI plus cetuximab or bevacizumab) before treatment start (baseline) and after secondary resection of metastases (post baseline). Changes of mutational profiles and tumor mutational burden (TMB) were assessed within a post-hoc analysis. Median overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) were compared between treatment arms. Paired tumor samples were obtained from 25 patients (19 RAS wild-type, 6 RAS mutant by pyrosequencing). ORR (92.0% vs 58.0%) and OS (60.8 vs 35.4 months, hazard ratio = 0.39 [95% CI 0.14-1.12], P = .08) were higher for patients receiving cetuximab. After conversion therapy, 56 alterations (42 in the cetuximab and 14 in the bevacizumab arm) were newly observed in 18 patients (9 each treated with cetuximab or bevacizumab). Gains (n = 21) and losses (n = 21) of alterations occurred during cetuximab-based treatment, while mainly gains of alterations occurred during bevacizumab (n = 10). Three of nine patients treated with cetuximab that presented a change of mutational profiles, developed resistance to cetuximab. Mutational profiles were largely comparable before and after treatment with anti-VEGF or anti-EGFR directed monoclonal antibodies after secondary resection. Mutations associated with resistance to anti-EGFR antibodies were observed in only one-third of patients.

Titel:	Mutational profiles of metastatic colorectal cancer treated with FOLFIRI plus cetuximab or bevacizumab before and after secondary resection (AIO KRK 0306; FIRE-3).
Autor/in / Beteiligte Person:	Stahler, A ; Heinemann, V ; Holch, JW ; von Einem JC ; Westphalen, CB ; Heinrich, K ; Schlieker, L ; Jelas, I ; Alig, AHS ; Fischer, LE ; Weiss, L ; Modest, DP ; von Weikersthal LF ; Decker, T ; Kiani, A ; Moehler, M ; Kaiser, F ; Kirchner, T ; Jung, A ; Stintzing, S
Link:	Full Text Finder (Volltext)
Zeitschrift:	International journal of cancer, Jg. 149 (2021-12-01), Heft 11, S. 1935-1943
Veröffentlichung:	1995- : New York, NY : Wiley-Liss ; <i>Original Publication</i>: 1966-1984 : Genève : International Union Against Cancer, 2021
Medientyp:	academicJournal
ISSN:	1097-0215 (electronic)
DOI:	10.1002/ijc.33747
Schlagwort:	Adult Aged Antineoplastic Agents, Immunological therapeutic use Biomarkers, Tumor genetics Camptothecin therapeutic use Colorectal Neoplasms secondary Colorectal Neoplasms surgery Female Fluorouracil therapeutic use Humans Leucovorin therapeutic use Male Middle Aged Proto-Oncogene Proteins p21(ras) genetics Retrospective Studies Treatment Outcome Antineoplastic Combined Chemotherapy Protocols therapeutic use Bevacizumab therapeutic use Camptothecin analogs & derivatives Cetuximab therapeutic use Colorectal Neoplasms drug therapy Colorectal Neoplasms genetics Mutation
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't Language: English [Int J Cancer] 2021 Dec 01; Vol. 149 (11), pp. 1935-1943. <i>Date of Electronic Publication: </i>2021 Jul 31. MeSH Terms: Mutation* ; Antineoplastic Combined Chemotherapy Protocols / therapeutic use ; Bevacizumab / therapeutic use ; Camptothecin / analogs & derivatives ; Cetuximab / therapeutic use ; Colorectal Neoplasms / drug therapy ; Colorectal Neoplasms / genetics ; Adult ; Aged ; Antineoplastic Agents, Immunological / therapeutic use ; Biomarkers, Tumor / genetics ; Camptothecin / therapeutic use ; Colorectal Neoplasms / secondary ; Colorectal Neoplasms / surgery ; Female ; Fluorouracil / therapeutic use ; Humans ; Leucovorin / therapeutic use ; Male ; Middle Aged ; Proto-Oncogene Proteins p21(ras) / genetics ; Retrospective Studies ; Treatment Outcome References: Van Cutsem E, Lenz HJ, Kohne CH, et al. 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Loss of chromosome 18q11.2-q12.1 is predictive for survival in patients with metastatic colorectal cancer treated with bevacizumab. J Clin Oncol. 2018;36:2052-2060. ; Adua D, Di Fabio F, Ercolani G, et al. Heterogeneity in the colorectal primary tumor and the synchronous resected liver metastases prior to and after treatment with an anti-EGFR monoclonal antibody. Mol Clin Oncol. 2017;7:113-120. ; Kovaleva V, Geissler AL, Lutz L, et al. Spatio-temporal mutation profiles of case-matched colorectal carcinomas and their metastases reveal unique de novo mutations in metachronous lung metastases by targeted next generation sequencing. Mol Cancer. 2016;15:63. ; Schweiger T, Liebmann-Reindl S, Glueck O, et al. Mutational profile of colorectal cancer lung metastases and paired primary tumors by targeted next generation sequencing: implications on clinical outcome after surgery. J Thorac Dis. 2018;10:6147-6157. ; Sutton PA, Jithesh PV, Jones RP, et al. Exome sequencing of synchronously resected primary colorectal tumours and colorectal liver metastases to inform oncosurgical management. Eur J Surg Oncol. 2018;44:115-121. ; Mogensen MB, Rossing M, Ostrup O, et al. Genomic alterations accompanying tumour evolution in colorectal cancer: tracking the differences between primary tumours and synchronous liver metastases by whole-exome sequencing. BMC Cancer. 2018;18:752. Contributed Indexing: Keywords: NGS; bevacizumab; cetuximab; metastatic colorectal cancer; paired samples Substance Nomenclature: 0 (Antineoplastic Agents, Immunological) ; 0 (Biomarkers, Tumor) ; 0 (KRAS protein, human) ; 2S9ZZM9Q9V (Bevacizumab) ; EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras)) ; PQX0D8J21J (Cetuximab) ; Q573I9DVLP (Leucovorin) ; U3P01618RT (Fluorouracil) ; XT3Z54Z28A (Camptothecin) SCR Protocol: IFL protocol Entry Date(s): Date Created: 20210726 Date Completed: 20211110 Latest Revision: 20211110 Update Code: 20240513

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Mutational profiles of metastatic colorectal cancer treated with FOLFIRI plus cetuximab or bevacizumab before and after secondary resection (AIO KRK 0306; FIRE-3).