Skip to main content
Top
Published in: Targeted Oncology 1/2022

01-01-2022 | Colorectal Cancer | Original Research Article

Prognostic Differences of RAS Mutations: Results from the South Australian Metastatic Colorectal Registry

Authors: Anas Alawawdeh, Cynthia Piantadosi, Amanda Rose Townsend, Christos Stelios Karapetis, Rob Padbury, Amitesh Chandra Roy, James Moore, Guy Maddern, David Roder, Annabelle Smith, Timothy Jay Price

Published in: Targeted Oncology | Issue 1/2022

Login to get access

Abstract

Background

Effective targeting of RAS mutations has proven elusive until recently. Novel agents directly targeting KRAS G12C have shown promise in early-phase clinical trials that included patients with metastatic colorectal cancer. Prior reports have suggested that G12C mutation may be predictive of poor outcome.

Objective

Assessment of the specific characteristics and prognostic implications of individual RAS mutation subtypes in patients with metastatic colorectal cancer.

Patients and methods

Retrospective review of individual RAS mutation types from the South Australian Metastatic Colorectal Registry between 2006 and 2020.

Results

Of the 5165 patients entered onto the registry, 2305 (45%) had RAS mutation results available. 772 (33%) had a RAS mutation. The nature of the RAS mutation was available in 668 (87% of those with RAS mutation). Rare mutations (outside codons 12 and 13) made up 12.6% of the total. There were numerical differences in survival between the specific RAS mutation subgroups, with the longest median overall survival (30 months) observed in those with G12S mutations. However, there was no statistical difference in survival when comparing the various RAS mutations, including the comparison of G12C to G12S (p = 0.38). Patients with cancer harbouring rare RAS mutations had a median survival of 30 months.

Conclusions

Whilst the G12S mutation was associated with the longest survival numerically, the observed survival for patients with the most common RAS mutations (G12C, G12V, G12A, G12D and G13D) did not significantly differ.
Literature
1.
go back to reference Ni D, Li X, He X, Zhang H, Zhang J, Lu S. Drugging K-RasG12C through covalent inhibitors: mission possible? Pharmacol Ther. 2019;202:1–7.CrossRef Ni D, Li X, He X, Zhang H, Zhang J, Lu S. Drugging K-RasG12C through covalent inhibitors: mission possible? Pharmacol Ther. 2019;202:1–7.CrossRef
2.
go back to reference Christensen JG, Olson P, Briere T, Wiel C, Bergo MO. Targeting Krasg12c-mutant cancer with a mutation-specific inhibitor. J Intern Med. 2020;288(2):183–91.CrossRef Christensen JG, Olson P, Briere T, Wiel C, Bergo MO. Targeting Krasg12c-mutant cancer with a mutation-specific inhibitor. J Intern Med. 2020;288(2):183–91.CrossRef
3.
go back to reference Bos JL. Ras oncogenes in human cancer: a review. Cancer Res. 1989;49:4682–9.PubMed Bos JL. Ras oncogenes in human cancer: a review. Cancer Res. 1989;49:4682–9.PubMed
4.
go back to reference Simanshu DK, Nissley DV, McCormick F. RAS proteins and their regulators in human disease. Cell. 2017;170:17–33.CrossRef Simanshu DK, Nissley DV, McCormick F. RAS proteins and their regulators in human disease. Cell. 2017;170:17–33.CrossRef
5.
go back to reference Cox AD, Fesik SW, Kimmelman AC, Luo J, Der CJ. Drugging the undruggable RAS: mission possible? Nat Rev Drug Discov. 2014;13(11):828–51.CrossRef Cox AD, Fesik SW, Kimmelman AC, Luo J, Der CJ. Drugging the undruggable RAS: mission possible? Nat Rev Drug Discov. 2014;13(11):828–51.CrossRef
6.
go back to reference Papke B, Der CJ. Drugging RAS: know the enemy. Science. 2017;355(6330):1158–63.CrossRef Papke B, Der CJ. Drugging RAS: know the enemy. Science. 2017;355(6330):1158–63.CrossRef
7.
go back to reference Ostrem JM, Shokat KM. Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design. Nat Rev Drug Discov. 2016;15(11):771.CrossRef Ostrem JM, Shokat KM. Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design. Nat Rev Drug Discov. 2016;15(11):771.CrossRef
8.
go back to reference Hammond DE, Mageean CJ, Rusilowicz EV, Wickenden JA, Clague MJ, Prior IA. Differential reprogramming of isogenic colorectal cancer cells by distinct activating KRAS mutations. J Proteome Res. 2015;14(3):1535–46.CrossRef Hammond DE, Mageean CJ, Rusilowicz EV, Wickenden JA, Clague MJ, Prior IA. Differential reprogramming of isogenic colorectal cancer cells by distinct activating KRAS mutations. J Proteome Res. 2015;14(3):1535–46.CrossRef
9.
go back to reference Modest DP, Ricard I, Heinemann V, Hegewisch-Becker S, Schmiegel W, Porschen R, et al. Outcome according to KRAS-, NRAS-and BRAF-mutation as well as KRAS mutation variants: pooled analysis of five randomized trials in metastatic colorectal cancer by the AIO colorectal cancer study group. Ann Oncol. 2016;27(9):1746–53.CrossRef Modest DP, Ricard I, Heinemann V, Hegewisch-Becker S, Schmiegel W, Porschen R, et al. Outcome according to KRAS-, NRAS-and BRAF-mutation as well as KRAS mutation variants: pooled analysis of five randomized trials in metastatic colorectal cancer by the AIO colorectal cancer study group. Ann Oncol. 2016;27(9):1746–53.CrossRef
10.
go back to reference Schirripa M, Nappo F, Cremolini C, Salvatore L, Rossini D, Bensi M, et al. KRAS G12C metastatic colorectal cancer: specific features of a new emerging target population. Clin Colorectal Cancer. 2020;19(3):219–25.CrossRef Schirripa M, Nappo F, Cremolini C, Salvatore L, Rossini D, Bensi M, et al. KRAS G12C metastatic colorectal cancer: specific features of a new emerging target population. Clin Colorectal Cancer. 2020;19(3):219–25.CrossRef
11.
go back to reference Jones RP, Sutton PA, Evans JP, Clifford R, McAvoy A, Lewis J, et al. Specific mutations in KRAS codon 12 are associated with worse overall survival in patients with advanced and recurrent colorectal cancer. Br J Cancer. 2017;116(7):923–9.CrossRef Jones RP, Sutton PA, Evans JP, Clifford R, McAvoy A, Lewis J, et al. Specific mutations in KRAS codon 12 are associated with worse overall survival in patients with advanced and recurrent colorectal cancer. Br J Cancer. 2017;116(7):923–9.CrossRef
12.
go back to reference Canon J, Rex K, Saiki AY, Mohr C, Cooke K, Bagal D, et al. The clinical KRAS (G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature. 2019;575(7781):217–23.CrossRef Canon J, Rex K, Saiki AY, Mohr C, Cooke K, Bagal D, et al. The clinical KRAS (G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature. 2019;575(7781):217–23.CrossRef
13.
go back to reference Hong DS, Fakih MG, Strickler JH, Desai J, Durm GA, Shapiro GI, et al. KRASG12C inhibition with sotorasib in advanced solid tumors. N Engl J Med. 2020;383(13):1207–17.CrossRef Hong DS, Fakih MG, Strickler JH, Desai J, Durm GA, Shapiro GI, et al. KRASG12C inhibition with sotorasib in advanced solid tumors. N Engl J Med. 2020;383(13):1207–17.CrossRef
14.
go back to reference Skoulidis F, Li BT, Dy GK, Price TJ, Falchook GS, Wolf J, et al. Sotorasib for Lung Cancers with KRAS p. G12C Mutation. N Engl J Med. 2021;384(25):2371–81.CrossRef Skoulidis F, Li BT, Dy GK, Price TJ, Falchook GS, Wolf J, et al. Sotorasib for Lung Cancers with KRAS p. G12C Mutation. N Engl J Med. 2021;384(25):2371–81.CrossRef
16.
go back to reference Weiss J, Yaeger RD, Johnson ML, Spira A, Klempner SJ, Barve MA, et al. LBA6 KRYSTAL-1: Adagrasib (MRTX849) as monotherapy or combined with cetuximab (Cetux) in patients (Pts) with colorectal cancer (CRC) harboring a KRASG12C mutation. Ann Oncol. 2021;32:S1294.CrossRef Weiss J, Yaeger RD, Johnson ML, Spira A, Klempner SJ, Barve MA, et al. LBA6 KRYSTAL-1: Adagrasib (MRTX849) as monotherapy or combined with cetuximab (Cetux) in patients (Pts) with colorectal cancer (CRC) harboring a KRASG12C mutation. Ann Oncol. 2021;32:S1294.CrossRef
17.
go back to reference Sakamoto K, Masutani T, Hirokawa T. Generation of KS-58 as the first K-Ras (G12D)-inhibitory peptide presenting anti-cancer activity in vivo. Sci Rep. 2020;10(1):1–6.CrossRef Sakamoto K, Masutani T, Hirokawa T. Generation of KS-58 as the first K-Ras (G12D)-inhibitory peptide presenting anti-cancer activity in vivo. Sci Rep. 2020;10(1):1–6.CrossRef
18.
go back to reference Lindsay CR, Garassino MC, Nadal E, Öhrling K, Scheffler M, Mazières J. On target: rational approaches to KRAS inhibition for treatment of non-small cell lung carcinoma. Lung Cancer. 2021;160:152–65.CrossRef Lindsay CR, Garassino MC, Nadal E, Öhrling K, Scheffler M, Mazières J. On target: rational approaches to KRAS inhibition for treatment of non-small cell lung carcinoma. Lung Cancer. 2021;160:152–65.CrossRef
19.
go back to reference Neo EL, Beeke C, Price T, Maddern G, Karapetis C, Luke C, et al. South Australian clinical registry for metastatic colorectal cancer. ANZ J Surg. 2011;81(5):352–7.CrossRef Neo EL, Beeke C, Price T, Maddern G, Karapetis C, Luke C, et al. South Australian clinical registry for metastatic colorectal cancer. ANZ J Surg. 2011;81(5):352–7.CrossRef
20.
go back to reference Sinicrope FA, Okamoto K, Kasi PM, Kawakami H. Molecular biomarkers in the personalized treatment of colorectal cancer. Clin Gastroenterol Hepatol. 2016;14(5):651–8.CrossRef Sinicrope FA, Okamoto K, Kasi PM, Kawakami H. Molecular biomarkers in the personalized treatment of colorectal cancer. Clin Gastroenterol Hepatol. 2016;14(5):651–8.CrossRef
21.
go back to reference Cremolini C, Loupakis F, Masi G, Zagonel V, Bergamo F, Salvatore L, et al. FOLFOXIRI plus bevacizumab (bev) versus FOLFIRI plus bev as first-line treatment of metastatic colorectal cancer (mCRC): updated survival results of the phase III TRIBE trial by the GONO group. J Clin Oncol. 2015;33(3_suppl):657.CrossRef Cremolini C, Loupakis F, Masi G, Zagonel V, Bergamo F, Salvatore L, et al. FOLFOXIRI plus bevacizumab (bev) versus FOLFIRI plus bev as first-line treatment of metastatic colorectal cancer (mCRC): updated survival results of the phase III TRIBE trial by the GONO group. J Clin Oncol. 2015;33(3_suppl):657.CrossRef
22.
go back to reference Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15(10):1065–75.CrossRef Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15(10):1065–75.CrossRef
23.
go back to reference André T, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, et al. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med. 2020;383(23):2207–18.CrossRef André T, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, et al. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med. 2020;383(23):2207–18.CrossRef
24.
go back to reference Neumann J, Zeindl-Eberhart E, Kirchner T, Jung A. Frequency and type of KRAS mutations in routine diagnostic analysis of metastatic colorectal cancer. Pathol Res Pract. 2009;205(12):858–62.CrossRef Neumann J, Zeindl-Eberhart E, Kirchner T, Jung A. Frequency and type of KRAS mutations in routine diagnostic analysis of metastatic colorectal cancer. Pathol Res Pract. 2009;205(12):858–62.CrossRef
25.
go back to reference Li W, Liu Y, Cai S, Yang C, Lin Z, Zhou L, et al. Not all mutations of KRAS predict poor prognosis in patients with colorectal cancer. Int J Clin Exp Pathol. 2019;12(3):957.PubMedPubMedCentral Li W, Liu Y, Cai S, Yang C, Lin Z, Zhou L, et al. Not all mutations of KRAS predict poor prognosis in patients with colorectal cancer. Int J Clin Exp Pathol. 2019;12(3):957.PubMedPubMedCentral
26.
go back to reference Henry JT, Coker O, Chowdhury S, Shen JP, Morris VK, Dasari A, et al. Comprehensive clinical and molecular characterization of KRAS G12C-mutant colorectal cancer. JCO Precis Oncol. 2021;5:613–21.CrossRef Henry JT, Coker O, Chowdhury S, Shen JP, Morris VK, Dasari A, et al. Comprehensive clinical and molecular characterization of KRAS G12C-mutant colorectal cancer. JCO Precis Oncol. 2021;5:613–21.CrossRef
27.
go back to reference Chida K, Kotani D, Masuishi T, Kawakami T, Kawamoto Y, Kato K, et al. The prognostic impact of KRAS G12C mutation in patients with metastatic colorectal cancer: a multicenter retrospective observational study. Oncologist. 2021;26(10):845–53.CrossRef Chida K, Kotani D, Masuishi T, Kawakami T, Kawamoto Y, Kato K, et al. The prognostic impact of KRAS G12C mutation in patients with metastatic colorectal cancer: a multicenter retrospective observational study. Oncologist. 2021;26(10):845–53.CrossRef
28.
go back to reference Ikoma T, Shimokawa M, Kotaka M, Matsumoto T, Nagai H, Boku S, et al. Clinical and prognostic features of patients with detailed RAS/BRAF-mutant colorectal cancer in Japan. BMC Cancer. 2021;21(1):1.CrossRef Ikoma T, Shimokawa M, Kotaka M, Matsumoto T, Nagai H, Boku S, et al. Clinical and prognostic features of patients with detailed RAS/BRAF-mutant colorectal cancer in Japan. BMC Cancer. 2021;21(1):1.CrossRef
29.
go back to reference Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM. K-Ras (G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature. 2013;503(7477):548–51.CrossRef Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM. K-Ras (G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature. 2013;503(7477):548–51.CrossRef
30.
go back to reference Kargbo RB. Inhibitors of G12C mutant Ras proteins for the treatment of cancers. ACS Med Chem Lett. 2019;10(1):10–1.CrossRef Kargbo RB. Inhibitors of G12C mutant Ras proteins for the treatment of cancers. ACS Med Chem Lett. 2019;10(1):10–1.CrossRef
31.
go back to reference Lito P, Solomon M, Li LS, Hansen R, Rosen N. Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism. Science. 2016;351(6273):604–8.CrossRef Lito P, Solomon M, Li LS, Hansen R, Rosen N. Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism. Science. 2016;351(6273):604–8.CrossRef
32.
go back to reference Sabari JK, Park H, Tolcher AW, Ou SH, Garon EB, George B, et al. KRYSTAL-2: a phase I/II trial of adagrasib (MRTX849) in combination with TNO155 in patients with advanced solid tumors with KRAS G12C mutation. J Clin Oncol. 2021;39(3_suppl):TPS146.CrossRef Sabari JK, Park H, Tolcher AW, Ou SH, Garon EB, George B, et al. KRYSTAL-2: a phase I/II trial of adagrasib (MRTX849) in combination with TNO155 in patients with advanced solid tumors with KRAS G12C mutation. J Clin Oncol. 2021;39(3_suppl):TPS146.CrossRef
33.
go back to reference Pietrantonio F, Yaeger R, Schrock AB, Randon G, Romero-Cordoba S, Rossini D, et al. Atypical RAS mutations in metastatic colorectal cancer. JCO Precis Oncol. 2019;3:1–1. Pietrantonio F, Yaeger R, Schrock AB, Randon G, Romero-Cordoba S, Rossini D, et al. Atypical RAS mutations in metastatic colorectal cancer. JCO Precis Oncol. 2019;3:1–1.
Metadata
Title
Prognostic Differences of RAS Mutations: Results from the South Australian Metastatic Colorectal Registry
Authors
Anas Alawawdeh
Cynthia Piantadosi
Amanda Rose Townsend
Christos Stelios Karapetis
Rob Padbury
Amitesh Chandra Roy
James Moore
Guy Maddern
David Roder
Annabelle Smith
Timothy Jay Price
Publication date
01-01-2022
Publisher
Springer International Publishing
Published in
Targeted Oncology / Issue 1/2022
Print ISSN: 1776-2596
Electronic ISSN: 1776-260X
DOI
https://doi.org/10.1007/s11523-021-00856-9

Other articles of this Issue 1/2022

Targeted Oncology 1/2022 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine