Association between specific mutations in KRAS codon 12 and colorectal liver metastasis

Georgios Antonios Margonis, Yuhree Kim, Gaya Spolverato, Aslam Ejaz, Rohan Gupta, David Cosgrove, Robert Anders, Georgios Karagkounis, Michael A. Choti, Timothy M. Pawlik

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

IMPORTANCE Currently, one of the most commonly available biomarkers in the treatment of patients with colorectal liver metastases (CRLM) is the Kirsten rat sarcoma viral oncogene homolog (KRAS); however, the prognostic implications of specific mutations of the KRAS gene are still not well defined. OBJECTIVE To investigate the prognostic impact of specific KRAS mutations on patients undergoing liver resection for CRLM. DESIGN, SETTING, AND PARTICIPANTS This retrospective single-center studywas conducted from January 1, 2003, to December 31, 2013. Data about specific KRAS mutations for 331 patients who underwent hepatic resection for CRLM at Johns Hopkins Hospital between 2003 and 2013 were analyzed. Clinicopathological characteristics, perioperative details, and outcomes were stratified by specific KRAS mutation at codons 12 and 13. INTERVENTION Resection of CRLM. MAIN OUTCOMES AND MEASURES Overall survival (OS) and recurrence-free survival. RESULTS A mutated KRAS (mtKRAS) was identified in 91 patients (27.5%). At a median follow-up of 27.4 months, recurrence was observed in 48 patients (52.7%) with mtKRAS and 130 patients (54.2%) with wild-type KRAS (wtKRAS) (P =.82). Median and 5-year survival among patients with mtKRAS was 32.4 months and 32.7%, respectively, vs 58.5 months and 46.9%, respectively, for patients with wtKRAS (P =.02). Patients with KRAS codon 12 mutations had worse OS (hazard ratio [HR], 1.54; 95%CI, 1.05-2.27; P =.03) vs those with wtKRAS, whereas a KRAS codon 13 mutation was not associated with prognosis (HR, 1.47; 95%CI, 0.83-2.62; P =.19). Among the 6 most common mutations in codons 12 and 13, only G12V (HR, 1.78; 95%CI, 1.00-3.17; P =.05) and G12S (HR, 3.33; 95%CI, 1.22-9.10; P =.02) were associated with worse OS compared with patients with wtKRAS (both P <.05). Among patients who recurred, G12V (HR, 2.96; 95%CI, 1.32-6.61; P =.01), G12C (HR, 6.74; 95%CI, 2.05-22.2; P =.002), and G12S mutations (HR, 4.91; 95%CI, 1.52-15.8; P =.01) were associated with worse OS (both P <.05).

Original languageEnglish (US)
Pages (from-to)722-729
Number of pages8
JournalJAMA Surgery
Volume150
Issue number8
DOIs
StatePublished - Aug 1 2015

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Codon
Neoplasm Metastasis
Mutation
Liver
Survival
Recurrence
Oncogenes
Sarcoma
Biomarkers
Outcome Assessment (Health Care)

ASJC Scopus subject areas

  • Surgery

Cite this

Margonis, G. A., Kim, Y., Spolverato, G., Ejaz, A., Gupta, R., Cosgrove, D., ... Pawlik, T. M. (2015). Association between specific mutations in KRAS codon 12 and colorectal liver metastasis. JAMA Surgery, 150(8), 722-729. https://doi.org/10.1001/jamasurg.2015.0313

Association between specific mutations in KRAS codon 12 and colorectal liver metastasis. / Margonis, Georgios Antonios; Kim, Yuhree; Spolverato, Gaya; Ejaz, Aslam; Gupta, Rohan; Cosgrove, David; Anders, Robert; Karagkounis, Georgios; Choti, Michael A.; Pawlik, Timothy M.

In: JAMA Surgery, Vol. 150, No. 8, 01.08.2015, p. 722-729.

Research output: Contribution to journalArticle

Margonis, GA, Kim, Y, Spolverato, G, Ejaz, A, Gupta, R, Cosgrove, D, Anders, R, Karagkounis, G, Choti, MA & Pawlik, TM 2015, 'Association between specific mutations in KRAS codon 12 and colorectal liver metastasis', JAMA Surgery, vol. 150, no. 8, pp. 722-729. https://doi.org/10.1001/jamasurg.2015.0313
Margonis GA, Kim Y, Spolverato G, Ejaz A, Gupta R, Cosgrove D et al. Association between specific mutations in KRAS codon 12 and colorectal liver metastasis. JAMA Surgery. 2015 Aug 1;150(8):722-729. https://doi.org/10.1001/jamasurg.2015.0313
Margonis, Georgios Antonios ; Kim, Yuhree ; Spolverato, Gaya ; Ejaz, Aslam ; Gupta, Rohan ; Cosgrove, David ; Anders, Robert ; Karagkounis, Georgios ; Choti, Michael A. ; Pawlik, Timothy M. / Association between specific mutations in KRAS codon 12 and colorectal liver metastasis. In: JAMA Surgery. 2015 ; Vol. 150, No. 8. pp. 722-729.
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abstract = "IMPORTANCE Currently, one of the most commonly available biomarkers in the treatment of patients with colorectal liver metastases (CRLM) is the Kirsten rat sarcoma viral oncogene homolog (KRAS); however, the prognostic implications of specific mutations of the KRAS gene are still not well defined. OBJECTIVE To investigate the prognostic impact of specific KRAS mutations on patients undergoing liver resection for CRLM. DESIGN, SETTING, AND PARTICIPANTS This retrospective single-center studywas conducted from January 1, 2003, to December 31, 2013. Data about specific KRAS mutations for 331 patients who underwent hepatic resection for CRLM at Johns Hopkins Hospital between 2003 and 2013 were analyzed. Clinicopathological characteristics, perioperative details, and outcomes were stratified by specific KRAS mutation at codons 12 and 13. INTERVENTION Resection of CRLM. MAIN OUTCOMES AND MEASURES Overall survival (OS) and recurrence-free survival. RESULTS A mutated KRAS (mtKRAS) was identified in 91 patients (27.5{\%}). At a median follow-up of 27.4 months, recurrence was observed in 48 patients (52.7{\%}) with mtKRAS and 130 patients (54.2{\%}) with wild-type KRAS (wtKRAS) (P =.82). Median and 5-year survival among patients with mtKRAS was 32.4 months and 32.7{\%}, respectively, vs 58.5 months and 46.9{\%}, respectively, for patients with wtKRAS (P =.02). Patients with KRAS codon 12 mutations had worse OS (hazard ratio [HR], 1.54; 95{\%}CI, 1.05-2.27; P =.03) vs those with wtKRAS, whereas a KRAS codon 13 mutation was not associated with prognosis (HR, 1.47; 95{\%}CI, 0.83-2.62; P =.19). Among the 6 most common mutations in codons 12 and 13, only G12V (HR, 1.78; 95{\%}CI, 1.00-3.17; P =.05) and G12S (HR, 3.33; 95{\%}CI, 1.22-9.10; P =.02) were associated with worse OS compared with patients with wtKRAS (both P <.05). Among patients who recurred, G12V (HR, 2.96; 95{\%}CI, 1.32-6.61; P =.01), G12C (HR, 6.74; 95{\%}CI, 2.05-22.2; P =.002), and G12S mutations (HR, 4.91; 95{\%}CI, 1.52-15.8; P =.01) were associated with worse OS (both P <.05).",
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T1 - Association between specific mutations in KRAS codon 12 and colorectal liver metastasis

AU - Margonis, Georgios Antonios

AU - Kim, Yuhree

AU - Spolverato, Gaya

AU - Ejaz, Aslam

AU - Gupta, Rohan

AU - Cosgrove, David

AU - Anders, Robert

AU - Karagkounis, Georgios

AU - Choti, Michael A.

AU - Pawlik, Timothy M.

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N2 - IMPORTANCE Currently, one of the most commonly available biomarkers in the treatment of patients with colorectal liver metastases (CRLM) is the Kirsten rat sarcoma viral oncogene homolog (KRAS); however, the prognostic implications of specific mutations of the KRAS gene are still not well defined. OBJECTIVE To investigate the prognostic impact of specific KRAS mutations on patients undergoing liver resection for CRLM. DESIGN, SETTING, AND PARTICIPANTS This retrospective single-center studywas conducted from January 1, 2003, to December 31, 2013. Data about specific KRAS mutations for 331 patients who underwent hepatic resection for CRLM at Johns Hopkins Hospital between 2003 and 2013 were analyzed. Clinicopathological characteristics, perioperative details, and outcomes were stratified by specific KRAS mutation at codons 12 and 13. INTERVENTION Resection of CRLM. MAIN OUTCOMES AND MEASURES Overall survival (OS) and recurrence-free survival. RESULTS A mutated KRAS (mtKRAS) was identified in 91 patients (27.5%). At a median follow-up of 27.4 months, recurrence was observed in 48 patients (52.7%) with mtKRAS and 130 patients (54.2%) with wild-type KRAS (wtKRAS) (P =.82). Median and 5-year survival among patients with mtKRAS was 32.4 months and 32.7%, respectively, vs 58.5 months and 46.9%, respectively, for patients with wtKRAS (P =.02). Patients with KRAS codon 12 mutations had worse OS (hazard ratio [HR], 1.54; 95%CI, 1.05-2.27; P =.03) vs those with wtKRAS, whereas a KRAS codon 13 mutation was not associated with prognosis (HR, 1.47; 95%CI, 0.83-2.62; P =.19). Among the 6 most common mutations in codons 12 and 13, only G12V (HR, 1.78; 95%CI, 1.00-3.17; P =.05) and G12S (HR, 3.33; 95%CI, 1.22-9.10; P =.02) were associated with worse OS compared with patients with wtKRAS (both P <.05). Among patients who recurred, G12V (HR, 2.96; 95%CI, 1.32-6.61; P =.01), G12C (HR, 6.74; 95%CI, 2.05-22.2; P =.002), and G12S mutations (HR, 4.91; 95%CI, 1.52-15.8; P =.01) were associated with worse OS (both P <.05).

AB - IMPORTANCE Currently, one of the most commonly available biomarkers in the treatment of patients with colorectal liver metastases (CRLM) is the Kirsten rat sarcoma viral oncogene homolog (KRAS); however, the prognostic implications of specific mutations of the KRAS gene are still not well defined. OBJECTIVE To investigate the prognostic impact of specific KRAS mutations on patients undergoing liver resection for CRLM. DESIGN, SETTING, AND PARTICIPANTS This retrospective single-center studywas conducted from January 1, 2003, to December 31, 2013. Data about specific KRAS mutations for 331 patients who underwent hepatic resection for CRLM at Johns Hopkins Hospital between 2003 and 2013 were analyzed. Clinicopathological characteristics, perioperative details, and outcomes were stratified by specific KRAS mutation at codons 12 and 13. INTERVENTION Resection of CRLM. MAIN OUTCOMES AND MEASURES Overall survival (OS) and recurrence-free survival. RESULTS A mutated KRAS (mtKRAS) was identified in 91 patients (27.5%). At a median follow-up of 27.4 months, recurrence was observed in 48 patients (52.7%) with mtKRAS and 130 patients (54.2%) with wild-type KRAS (wtKRAS) (P =.82). Median and 5-year survival among patients with mtKRAS was 32.4 months and 32.7%, respectively, vs 58.5 months and 46.9%, respectively, for patients with wtKRAS (P =.02). Patients with KRAS codon 12 mutations had worse OS (hazard ratio [HR], 1.54; 95%CI, 1.05-2.27; P =.03) vs those with wtKRAS, whereas a KRAS codon 13 mutation was not associated with prognosis (HR, 1.47; 95%CI, 0.83-2.62; P =.19). Among the 6 most common mutations in codons 12 and 13, only G12V (HR, 1.78; 95%CI, 1.00-3.17; P =.05) and G12S (HR, 3.33; 95%CI, 1.22-9.10; P =.02) were associated with worse OS compared with patients with wtKRAS (both P <.05). Among patients who recurred, G12V (HR, 2.96; 95%CI, 1.32-6.61; P =.01), G12C (HR, 6.74; 95%CI, 2.05-22.2; P =.002), and G12S mutations (HR, 4.91; 95%CI, 1.52-15.8; P =.01) were associated with worse OS (both P <.05).

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