Top

Published in:

01-03-2015 | Hepatobiliary Tumors

RAS Mutations Predict Radiologic and Pathologic Response in Patients Treated with Chemotherapy Before Resection of Colorectal Liver Metastases

Authors: Yoshihiro Mise, MD, PhD, Giuseppe Zimmitti, MD, Junichi Shindoh, MD, PhD, Scott Kopetz, MD, Evelyne M. Loyer, MD, Andreas Andreou, MD, Amanda B. Cooper, MD, Harmeet Kaur, MD, Thomas A. Aloia, MD, Dipen M. Maru, MD, Jean-Nicolas Vauthey, MD

Published in: Annals of Surgical Oncology | Issue 3/2015

Abstract

Background

RAS mutations have been reported to be a potential prognostic factor in patients with colorectal liver metastases (CLM). However, the impact of RAS mutations on response to chemotherapy remains unclear. The purpose of this study was to investigate the correlation between RAS mutations and response to preoperative chemotherapy and their impact on survival in patients undergoing curative resection of CLM.

Methods

RAS mutational status was assessed and its relation to morphologic response and pathologic response was investigated in 184 patients meeting inclusion criteria. Predictors of survival were assessed. The prognostic impact of RAS mutational status was then analyzed using two different multivariate models, including either radiologic morphologic response (model 1) or pathologic response (model 2).

Results

Optimal morphologic response and major pathologic response were more common in patients with wild-type RAS (32.9 and 58.9 %, respectively) than in patients with RAS mutations (10.5 and 36.8 %; P = 0.006 and 0.015, respectively). Multivariate analysis confirmed that wild-type RAS was a strong predictor of optimal morphologic response [odds ratio (OR), 4.38; 95 % CI 1.45–13.15] and major pathologic response (OR, 2.61; 95 % CI 1.17–5.80). RAS mutations were independently correlated with both overall survival and recurrence free-survival (hazard ratios, 3.57 and 2.30, respectively, in model 1, and 3.19 and 2.09, respectively, in model 2). Subanalysis revealed that RAS mutational status clearly stratified survival in patients with inadequate response to preoperative chemotherapy.

Conclusions

RAS mutational status can be used to complement the current prognostic indicators for patients undergoing curative resection of CLM after preoperative modern chemotherapy.

Kopetz S, Chang GJ, Overman MJ, et al. Improved survival in metastatic colorectal cancer is associated with adoption of hepatic resection and improved chemotherapy. J Clin Oncol. 2009;27(22):3677–83.PubMedCentralPubMedCrossRef

Kopetz S, Vauthey JN. Perioperative chemotherapy for resectable hepatic metastases. Lancet. 2008;371(9617):963–5.PubMedCrossRef

Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg. 1999;230(3):309–18.PubMedCentralPubMedCrossRef

Iwatsuki S, Dvorchik I, Madariaga JR, et al. Hepatic resection for metastatic colorectal adenocarcinoma: a proposal of a prognostic scoring system. J Am Coll Surg. 1999;189(3):291–9.PubMedCentralPubMedCrossRef

Nordlinger B, Guiguet M, Vaillant JC, et al. Surgical resection of colorectal carcinoma metastases to the liver. A prognostic scoring system to improve case selection, based on 1568 patients. Association Francaise de Chirurgie. Cancer. 1996;77(7):1254–62.PubMedCrossRef

Rees M, Tekkis PP, Welsh FK, O’Rourke T, John TG. Evaluation of long-term survival after hepatic resection for metastatic colorectal cancer: a multifactorial model of 929 patients. Ann Surg. 2008;247(1):125–35.PubMedCrossRef

Jarnagin WR. Clinical scoring systems for stratifying risk after resection of hepatic colorectal metastases: still relevant? Ann Surg Oncol. 2011;18(10):2711–3.PubMedCrossRef

Tomlinson JS, Jarnagin WR, DeMatteo RP, et al. Actual 10-year survival after resection of colorectal liver metastases defines cure. J Clin Oncol. 2007;25(29):4575–80.PubMedCrossRef

Blazer DG, 3rd, Kishi Y, Maru DM, et al. Pathologic response to preoperative chemotherapy: a new outcome end point after resection of hepatic colorectal metastases. J Clin Oncol. 2008;26(33):5344–51.PubMedCrossRef

10.

Chun YS, Vauthey JN, Boonsirikamchai P, et al. Association of computed tomography morphologic criteria with pathologic response and survival in patients treated with bevacizumab for colorectal liver metastases. JAMA. 2009;302(21):2338–44.PubMedCentralPubMedCrossRef

11.

Shindoh J, Loyer EM, Kopetz S, et al. Optimal morphologic response to preoperative chemotherapy: an alternate outcome end point before resection of hepatic colorectal metastases. J Clin Oncol. 2012;30(36):4566–72.PubMedCentralPubMedCrossRef

12.

Bos JL, Fearon ER, Hamilton SR, et al. Prevalence of ras gene mutations in human colorectal cancers. Nature. 1987;327(6120):293–7.PubMedCrossRef

13.

Vogelstein B, Fearon ER, Hamilton SR, et al. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988;319(9):525–32.PubMedCrossRef

14.

Andreyev HJ, Norman AR, Cunningham D, Oates JR, Clarke PA. Kirsten ras mutations in patients with colorectal cancer: the multicenter “RASCAL” study. J Natl Cancer Inst. 1998;90(9):675–84.PubMedCrossRef

15.

Watanabe T, Wu TT, Catalano PJ, et al. Molecular predictors of survival after adjuvant chemotherapy for colon cancer. N Engl J Med. 2001;344(16):1196–206.PubMedCentralPubMedCrossRef

16.

De Roock W, Claes B, Bernasconi D, et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol. 2010;11(8):753–62.PubMedCrossRef

17.

Lievre A, Bachet JB, Le Corre D, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 2006;66(8):3992–5.PubMedCrossRef

18.

Van Cutsem E, Kohne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360(14):1408–17.PubMedCrossRef

19.

Nash GM, Gimbel M, Shia J, et al. KRAS mutation correlates with accelerated metastatic progression in patients with colorectal liver metastases. Ann Surg Oncol. 2010;17(2):572–8.PubMedCrossRef

20.

Stremitzer S, Stift J, Gruenberger B, et al. KRAS status and outcome of liver resection after neoadjuvant chemotherapy including bevacizumab. Br J Surg. 2012;99(11):1575–82.PubMedCrossRef

21.

Andreou A, Aloia TA, Brouquet A, et al. Margin status remains an important determinant of survival after surgical resection of colorectal liver metastases in the era of modern chemotherapy. Ann Surg. 2013;257(6):1079–88.PubMedCentralPubMedCrossRef

22.

Stemke-Hale K, Gonzalez-Angulo AM, Lluch A, et al. An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res. 2008;68(15):6084–91.PubMedCentralPubMedCrossRef

23.

Gabriel S, Ziaugra L, Tabbaa D. SNP genotyping using the Sequenom MassARRAY iPLEX platform. Curr Protoc Hum Genet. 2009;Chapter 2(Unit 2):12.

24.

Thomas RK, Baker AC, Debiasi RM, et al. High-throughput oncogene mutation profiling in human cancer. Nat Genet. 2007;39(3):347–51.PubMedCrossRef

25.

Pearce M, Ehrich M. Somatic Mutation Analysis in Tumor Samples using the Sequenom. MassARRAY^® System. 2011http://www.nature.com/app_notes/nmeth/2010/101304/full/an7545.html.

26.

Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47.PubMedCrossRef

27.

Rubbia-Brandt L, Giostra E, Brezault C, et al. Importance of histological tumor response assessment in predicting the outcome in patients with colorectal liver metastases treated with neo-adjuvant chemotherapy followed by liver surgery. Ann Oncol. 2007;18(2):299–304.PubMedCrossRef

28.

Poultsides GA, Bao F, Servais EL, et al. Pathologic response to preoperative chemotherapy in colorectal liver metastases: fibrosis, not necrosis, predicts outcome. Ann Surg Oncol. 2012;19(9):2797–804.PubMedCrossRef

29.

Folprecht G, Gruenberger T, Bechstein WO, et al. Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial. Lancet Oncol. 2010;11(1):38–47.PubMedCrossRef

30.

Vauthey JN, Zimmitti G, Kopetz SE, et al. RAS mutation status predicts survival and patterns of recurrence in patients undergoing hepatectomy for colorectal liver metastases. Ann Surg. 2013;258(4):619–27.

31.

Lau LF, Williams DS, Lee ST, et al. Metabolic response to preoperative chemotherapy predicts prognosis for patients undergoing surgical resection of colorectal cancer metastatic to the liver. Ann Surg Oncol. 2014;21(7):2420–8.PubMedCrossRef

32.

Piessevaux H, Buyse M, Schlichting M, et al. Use of early tumor shrinkage to predict long-term outcome in metastatic colorectal cancer treated with cetuximab. J Clin Oncol. 2013;31(30):3764–75.PubMedCrossRef

33.

Santini D, Loupakis F, Vincenzi B, et al. High concordance of KRAS status between primary colorectal tumors and related metastatic sites: implications for clinical practice. Oncologist. 2008;13(12):1270–5.PubMedCrossRef

34.

Knijn N, Mekenkamp LJ, Klomp M, et al. KRAS mutation analysis: a comparison between primary tumours and matched liver metastases in 305 colorectal cancer patients. Br J Cancer. 2011;104(6):1020–6.PubMedCentralPubMedCrossRef

35.

Italiano A, Hostein I, Soubeyran I, et al. KRAS and BRAF mutational status in primary colorectal tumors and related metastatic sites: biological and clinical implications. Ann Surg Oncol. 2010;17(5):1429–34.PubMedCrossRef

36.

Etienne-Grimaldi MC, Formento JL, Francoual M, et al. K-Ras mutations and treatment outcome in colorectal cancer patients receiving exclusive fluoropyrimidine therapy. Clin Cancer Res. 2008;14(15):4830–5.PubMedCrossRef

37.

Oudejans JJ, Slebos RJ, Zoetmulder FA, Mooi WJ, Rodenhuis S. Differential activation of ras genes by point mutation in human colon cancer with metastases to either lung or liver. Int J Cancer. 1991;49(6):875–9.PubMedCrossRef

Title: RAS Mutations Predict Radiologic and Pathologic Response in Patients Treated with Chemotherapy Before Resection of Colorectal Liver Metastases
Authors: Yoshihiro Mise, MD, PhD
Giuseppe Zimmitti, MD
Junichi Shindoh, MD, PhD
Scott Kopetz, MD
Evelyne M. Loyer, MD
Andreas Andreou, MD
Amanda B. Cooper, MD
Harmeet Kaur, MD
Thomas A. Aloia, MD
Dipen M. Maru, MD
Jean-Nicolas Vauthey, MD
Publication date: 01-03-2015
Publisher: Springer US
Published in: Annals of Surgical Oncology / Issue 3/2015
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI: https://doi.org/10.1245/s10434-014-4042-6

At a glance: The STEP trials

Springer Medicine

RAS Mutations Predict Radiologic and Pathologic Response in Patients Treated with Chemotherapy Before Resection of Colorectal Liver Metastases

Abstract

Background

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 3/2015

A Prognostic Scoring System for Patients with Multiple Hepatocellular Carcinomas Treated by Hepatectomy

Impact of Pretreatment Imaging on Survival of Esophagectomy After Induction Therapy for Esophageal Cancer: Who Should be Given the Benefit of the Doubt?

The Training and Certification of Surgical Oncologists Globally

Coupling of Prostate and Thyroid Cancer Diagnoses in the United States

Global Surgical Oncology Disease Burden: Addressing Disparities Via Global Surgery Initiatives: The University of Michigan International Breast Cancer Registry

Surgical Management of Advanced Pancreatic Neuroendocrine Tumors: Short-Term and Long-Term Results from an International Multi-institutional Study