Colorectal cancer remains one of the most frequently diagnosed cancers in the developed world. The advent of new therapeutic agents has further expanded our treatment options. Epidermal growth factor receptor (EGFR) inhibitors have been shown to improve survival in metastatic cancer. However, there remain a substantial proportion of patients who do not benefit from this treatment. KRAS mutation status has been validated to predict the response to EGFR inhibitors with mutant status predicting non-responders. The validation of other predictive and prognostic markers will result in further optimization of the care plan for patient with colorectal cancer; maximising benefits while minimising toxicities. This article aims to provide an update of the various molecular markers for use in detection, prognostication and predicting responses in colon cancer.
JonkerDJO'CallaghanCJKarapetisCSZalcbergJRTuDAuHJ. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007;15;357(20):2040–8.
4.
Van CutsemEPeetersMSienaSHumbletYHendliszANeynsB. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007 May 1;25(13):1658–64.
5.
CunninghamDHumbletYSienaSKhayatDBleibergHSantoroA. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004 Jul 22;351(4):337–45.
6.
Van CutsemEKöhneCHHitreEZaluskiJChienCR ChangMakhsonA. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009; 2;360(14):1408–17.
7.
FolprechtGGruenbergerTBechsteinWORaabHRLordickFHartmannJT. 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.
8.
LièvreABachetJBLe CorreDBoigeVLandiBEmileJF. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 2006;15;66(8):3992–5.
9.
LièvreABachetJBBoigeVCayreALe CorreDBucE. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol. 2008; 20;26(3):374–9.
10.
Di FioreFBlanchardFCharbonnierFLe PessotFLamyAGalaisMP. Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by Cetuximab plus chemotherapy. Br J Cancer. 2007;23;96(8):1166–9.
11.
De RoockWPiessevauxHDe SchutterJJanssensMDe HertoghGPersoneniN. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol. 2008;19(3):508–15.
12.
KarapetisCSKhambata-FordSJonkerDJO'CallaghanCJTuDTebbuttNC. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359(17):1757–65.
13.
AmadoRGWolfMPeetersMVan CutsemESienaSFreemanDJ. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26(10):1626–34.
14.
BokemeyerCBondarenkoIMakhsonAHartmannJTAparicioJde BraudF. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009; 10;27(5):663–71.
15.
MaughanT. S.AdamsR.SmithC. G.SeymourM. T.WilsonR. H.MeadeA. M., Oxaliplatin and fluoropyrimidine chemotherapy plus or minus cetuximab: The effect of infusional 5-FU or capecitabine on the outcomes of the MRC COIN trial in advanced colorectal cancer (ACRC). Program and abstracts of the 2010 Gastrointestinal Cancers Symposium; 2010;22–24.
16.
SienaSCassideyJTaberneroJBurkesRLBarugelMEHumbletY. Randomized phase III study of panitumumab with FOLFOX4 compared to FOLFOX4 alone as first-line treatment for metastatic colorectal cancer: PRIME trial. ASCO GI Symposium. 2010p; abstr 283.
17.
PeetersMPriceTJHotkoYSCervantes-RuiperezADucreuxMAndreT. Randomized phase III study of panitumumab with FOLFIRI versus FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer (mCRC): Patient-reported outcomes. ASCO GI Symposium 2010; abstr 282.
18.
HechtJRMitchellEChidiacTScrogginCHagenstadCSpigelD. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol. 2009;10;27(5):672–80.
19.
RichmanSDSeymourMTChambersPElliottFDalyCLMeadeAM. KRAS and BRAF mutations in advanced colorectal cancer are associated with poor prognosis but do not preclude benefit from oxaliplatin or irinotecan: Results from the MRC FOCUS trial. J Clin Oncol. 2009;10;27(35):5931–7.
20.
Di NicolantonioFMartiniMMolinariFSartore-BianchiAArenaSSalettiP. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol. 2008;10;26(35):5705–12.
21.
SouglakosJPhilipsJWangRMarwahSSilverMTzardiM. Prognostic and predictive value of common mutations for treatment response and survival in patients with metastatic colorectal cancer. Br J Cancer. 2009 Aug 4;101(3):465–72.
22.
Fariña-SarasquetaAvan LijnschotenGMoerlandECreemersGJLemmensVERuttenHJ. The BRAF V600E mutation is an independent prognostic factor for survival in stage II and stage III colon cancer patients. Ann Oncol. 2010;21 (12) 2396–402.
23.
BardelliASienaS. Molecular mechanisms of resistance to cetuximab and panitumumab in colorectal cancer. J Clin Oncol. 2010 Mar 1;28(7):1254–61.
24.
FrattiniMSalettiPRomagnaniEMartinVMolinariFGhislettaM. PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients. Br J Cancer. 2007;97(8):1139–45.
25.
Sartore-BianchiAMartiniMMolinariFVeroneseSNichelattiMArtaleS. PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res. 2009;69(5):1851–7.
26.
RibicCMSargentDJMooreMJThibodeauSNFrenchAJGoldbergRM. Tumor microsatellite-instability status as a predictor of benefit from fluorouracilbased adjuvant chemotherapy for colon cancer. N Engl J Med. 2003;349(3):247–57.
27.
GryfeRKimHHsiehETAronsonMDHolowatyEJBullSB. Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med. 2000;342(2):69–77.
28.
PopatSHubnerRHoulstonRS. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol. 2005 Jan 20;23(3):609–18.
29.
SargentDJMarsoniSMongesGThibodeauSNLabiancaRHamiltonSR. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol. 2010 Jul 10;28(20):3219–26.
30.
BertagnolliMMNiedzwieckiDComptonCCHahnHPHallMDamasB. Microsatellite instability predicts improved response to adjuvant therapy with irinotecan, fluorouracil, and leucovorin in stage III colon cancer: Cancer and Leukemia Group B Protocol 89803. J Clin Oncol. 2009 Apr 10;27(11):1814–21.
31.
TejparSBosmanFDelorenziMFioccaRYanPKlingbielD. Microsatellite instability (MSI) in stage II and III colon cancer treated with 5FU-LV or 5FU-LV and irinotecan (PETACC 3-EORTC 40993-SAKK 60/00 trial). Proc ASCO Meeting Abstracts. J Clin Oncol. 2009; 27:15s: 4001.
32.
VasenHFMösleinGAlonsoABernsteinIBertarioLBlancoI. Guidelines for the clinical management of Lynch syndrome (hereditary nonpolyposis cancer). J Med Genet. 2007;44(6):353–62.
33.
WatanabeTWuTTCatalanoPJUekiTSatrianoRHallerDG. Molecular Predictors of Survival after Adjuvant Chemotherapy for Colon Cancer. N Engl J Med. 2001; 344:1196–206.
34.
PopatSHoulstonRS. A systematic review and meta-analysis of the relationship between chromosome 18q genotype, DCC status and colorectal cancer prognosis. Eur J Cancer. 2005;41(14):2060–70.
35.
ShirotaYStoehlmacherJBrabenderJXiongYPUetakeHDanenbergKD. ERCC1 and Thymidylate Synthase mRNA Levels Predict Survival for Colorectal Cancer Patients Receiving Combination Oxaliplatin and Fluorouracil Chemotherapy. J Clin Oncol. 2001;19(23):4298–304.
36.
PopatSMatakidouAHoulstonRS. Thymidylate Synthase Expression and Prognosis in Colorectal Cancer: A Systematic Review and Meta-Analysis. J Clin Oncol. 2004;22(3):529–36.
37.
LeeAEzzeldinHFourieJDiasioR. Dihydropyrimidine dehydrogenase deficiency: Impact of pharmacogenetics on 5-fluorouracil therapy. Clin Adv Hematol Oncol. 2004 Aug;2(8):527–32.
38.
SoongRShahNSalto-TellezMTaiBCSooRAHanHC. Prognostic significance of thymidylate synthase, dihydropyrimidine dehydrogenase and thymidine phosphorylase protein expression in colorectal cancer patients treated with or without 5-fluorouracil-based chemotherapy. Ann Oncol. 2008;19(5):915–9.
39.
PalomakiGEBradleyLADouglasMPKolorKDotsonWD. Can UGT1A1 genotyping reduce morbidity and mortality in patients with metastatic colorectal cancer treated with irinotecan? An evidence-based review. Genet Med. 2009;11(1):21–34.
40.
NingY.LurjeG.DanenbergK.CoocJ.YangD.PohlA., VEGF and VEGFR1 gene expression levels and tumor recurrence in adjuvant colon cancer. J Clin Oncol2009; 27:15s, (suppl; abstr 4040).
41.
El-KhoueiryA. B.PohlA.DanenbergK.CoocJ.ZhangW.YangD., Wt Kras and gene expression levels of VEGFR2, EGFR, and ERCC-1 associated with progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC) treated with first-line 5-FU or capecitabine with oxaliplatin and bevacizumab (FOLFOX/BV or XELOX/BV). J Clin Oncol. 2009; 27:15s.
42.
LurjeGHendifarAESchultheisAMPohlAHusainHYangD. Polymorphisms in interleukin 1 beta and interleukin 1 receptor antagonist associated with tumor recurrence in stage II colon cancer. Pharmacogenet Genomics. 2009;19(2):95–102.
43.
LurjeGZhangWSchultheisAMYangDGroshenSHendifarAE. Polymorphisms in VEGF and IL-8 predict tumor recurrence in stage III colon cancer. Ann Oncol. 2008;19(10):1734–41.
