Colorectal cancer is a heterogeneous disease, at the intertumoural and intratumoural level, with molecularly-defined subgroups that differ in their prognosis and response to treatment
Currently, only DNA mismatch-repair status, RAS-mutation and possibly BRAF-mutation status influence clinical decision-making, although the number of prognostic/predictive biomarkers is increasing
A transcriptome-based classification of CRC into four consensus molecular subtypes, which differ in their biology and prognosis, and probably also in their responsiveness to treatment, has been reported
International collaborations and innovative study designs are warranted to drive progress in the clinical development of subgroup-specific treatments
In recent years, the high heterogeneity of colorectal cancer (CRC) has become evident. Hence, biomarkers need to be developed that enable the stratification of patients with CRC into different prognostic subgroups and in relation to response to therapies, according to the distinctive tumour biology. Currently, only RAS-mutation status is used routinely as a negative predictive marker to avoid treatment with anti-EGFR agents in patients with metastatic CRC, and mismatch-repair status can guide the use of adjuvant chemotherapy in patients with early stage colon cancer. Advances in molecular biology over the past decade have enabled a better understanding of the development of CRC, as well as the more-precise use of innovative targeted therapies for this disease, and include three fundamental achievements. First, the availability of large databases to capture and store the genomic landscape of patients with CRC, providing information on the genes that are frequently deregulated in CRC. Second, the possibility of using gene-expression profiling to differentiate the subtypes of CRC into prognostic groups. Third, results from highly sensitive next-generation sequencing analyses have led to an appreciation of the extensive intratumoural heterogeneity of CRC. Herein, we discuss these advances and place them into the clinical context, and present the novel targets and therapeutic opportunities that are on the horizon.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Identification of genes with high heterogeneity of expression as a predictor of different prognosis and therapeutic responses in colorectal cancer: a challenge and a strategy
Cancer Cell International Open Access 05 September 2022
DDX39B drives colorectal cancer progression by promoting the stability and nuclear translocation of PKM2
Signal Transduction and Targeted Therapy Open Access 17 August 2022
A novel long noncoding RNA SP100-AS1 induces radioresistance of colorectal cancer via sponging miR-622 and stabilizing ATG3
Cell Death & Differentiation Open Access 17 August 2022
Subscribe to Journal
Get full journal access for 1 year
only $8.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Vermeulen, L. et al. Defining stem cell dynamics in models of intestinal tumor initiation. Science 342, 995–998 (2013).
Fearon, E. R. Molecular genetics of colorectal cancer. Annu. Rev. Pathol. 6, 479–507 (2011).
Markowitz, S. D. & Bertagnolli, M. M. Molecular origins of cancer: molecular basis of colorectal cancer. N. Engl. J. Med. 361, 2449–2460 (2009).
Fearon, E. R. & Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell 61, 759–767 (1990).
Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330–337 (2012).
Wood, L. D. et al. The genomic landscapes of human breast and colorectal cancers. Science 318, 1108–1113 (2007).
IJspeert, J. E., Vermeulen, L., Meijer, G. A. & Dekker, E. Serrated neoplasia — role in colorectal carcinogenesis and clinical implications. Nat. Rev. Gastroenterol. Hepatol. 12, 401–409 (2015).
Leedham, S. J. et al. Clonality, founder mutations, and field cancerization in human ulcerative colitis-associated neoplasia. Gastroenterology 136, 542–550.e6 (2009).
Hussain, S. P. et al. Increased p53 mutation load in noncancerous colon tissue from ulcerative colitis: a cancer-prone chronic inflammatory disease. Cancer Res. 60, 3333–3337 (2000).
De Sousa, E. M. F. et al. Poor-prognosis colon cancer is defined by a molecularly distinct subtype and develops from serrated precursor lesions. Nat. Med. 19, 614–618 (2013).
Boland, C. R. & Goel, A. Microsatellite instability in colorectal cancer. Gastroenterology 138, 2073–2087.e3 (2010).
Andre, T. et al. Adjuvant fluorouracil, leucovorin, and oxaliplatin in stage II to III colon cancer: updated 10-year survival and outcomes according to BRAF mutation and mismatch repair status of the MOSAIC study. J. Clin. Oncol. 33, 4176–4187 (2015).
Van Gijn, W. et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial. Lancet Oncol. 12, 575–582 (2011).
Bosset, J. F. et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N. Engl. J. Med. 355, 1114–1123 (2006).
Sugai, T. et al. Analysis of molecular alterations in left- and right-sided colorectal carcinomas reveals distinct pathways of carcinogenesis: proposal for new molecular profile of colorectal carcinomas. J. Mol. Diagn. 8, 193–201 (2006).
Breugom, A. J. et al. Adjuvant chemotherapy after preoperative (chemo)radiotherapy and surgery for patients with rectal cancer: a systematic review and meta-analysis of individual patient data. Lancet Oncol. 16, 200–207 (2015).
Sargent, D. J. et al. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J. Clin. Oncol. 28, 3219–3226 (2010).
Allegra, C. J. et al. Bevacizumab in stage II–III colon cancer: 5-year update of the National Surgical Adjuvant Breast and Bowel Project C-08 trial. J. Clin. Oncol. 31, 359–364 (2013).
Alberts, S. R. et al. Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: a randomized trial. JAMA 307, 1383–1393 (2012).
Pahlman, L. A. et al. Should the benefit of adjuvant chemotherapy in colon cancer be re-evaluated? J. Clin. Oncol. 34, 1297–1299 (2016).
Huiskens, J. et al. Treatment strategies in colorectal cancer patients with initially unresectable liver-only metastases, a study protocol of the randomised phase 3 CAIRO5 study of the Dutch Colorectal Cancer Group (DCCG). BMC Cancer 15, 365 (2015).
Meyerhardt, J. A. & Mayer, R. J. Systemic therapy for colorectal cancer. N. Engl. J. Med. 352, 476–487 (2005).
Mayer, R. J. et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N. Engl. J. Med. 372, 1909–1919 (2015).
Koopman, M. et al. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet 370, 135–142 (2007).
Seymour, M. T. et al. Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial. Lancet 370, 143–152 (2007).
Loupakis, F. et al. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N. Engl. J. Med. 371, 1609–1618 (2014).
Hurwitz, H. et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N. Engl. J. Med. 350, 2335–2342 (2004).
Kabbinavar, F. F. et al. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J. Clin. Oncol. 23, 3697–3705 (2005).
Saltz, L. B. et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J. Clin. Oncol. 26, 2013–2019 (2008).
Douillard, J. Y. et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J. Clin. Oncol. 28, 4697–4705 (2010).
Van Cutsem, E. et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N. Engl. J. Med. 360, 1408–1417 (2009).
Amado, R. G. et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J. Clin. Oncol. 26, 1626–1634 (2008).
Karapetis, C. S. et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N. Engl. J. Med. 359, 1757–1765 (2008).
Van Cutsem, E. et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J. Clin. Oncol. 30, 3499–3506 (2012).
Tabernero, J. et al. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 16, 499–508 (2015).
Grothey, A. et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381, 303–312 (2013).
Heinemann, V. 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. 15, 1065–1075 (2014).
Khattak, M. A., Martin, H., Davidson, A. & Phillips, M. Role of first-line anti-epidermal growth factor receptor therapy compared with anti-vascular endothelial growth factor therapy in advanced colorectal cancer: a meta-analysis of randomized clinical trials. Clin. Colorectal Cancer 14, 81–90 (2015).
Venook, A. et al. CALGB/SWOG 80405: phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC) [abstract]. J. Clin. Oncol. 32 (Suppl.), LBA3 (2014).
Grothey, A., Sargent, D., Goldberg, R. M. & Schmoll, H. J. Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J. Clin. Oncol. 22, 1209–1214 (2004).
Van Cutsem, E. et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann. Oncol. 27, 1386–1422 (2016).
Simkens, L. H. et al. Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group. Lancet 385, 1843–1852 (2015).
Hegewisch-Becker, S. et al. Maintenance strategies after first-line oxaliplatin plus fluoropyrimidine plus bevacizumab for patients with metastatic colorectal cancer (AIO 0207): a randomised, non-inferiority, open-label, phase 3 trial. Lancet Oncol. 16, 1355–1369 (2015).
Cunningham, D. et al. Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label, randomised phase 3 trial. Lancet Oncol. 14,1077–1085 (2013).
Meguid, R. A., Slidell, M. B., Wolfgang, C. L., Chang, D. C. & Ahuja, N. Is there a difference in survival between right- versus left-sided colon cancers? Ann. Surg. Oncol. 15, 2388–2394 (2008).
Benedix, F. et al. Comparison of 17,641 patients with right- and left-sided colon cancer: differences in epidemiology, perioperative course, histology, and survival. Dis. Colon Rectum 53, 57–64 (2010).
Weiss, J. M. et al. Mortality by stage for right- versus left-sided colon cancer: analysis of surveillance, epidemiology, and end results — Medicare data. J. Clin. Oncol. 29, 4401–4409 (2011).
Loupakis, F. et al. Primary tumor location as a prognostic factor in metastatic colorectal cancer. J. Natl Cancer Inst. 107, dju427 (2015).
Lee, G. H. et al. Is right-sided colon cancer different to left-sided colorectal cancer? — a systematic review. Eur. J. Surg. Oncol. 41, 300–308 (2015).
Walther, A. et al. Genetic prognostic and predictive markers in colorectal cancer. Nat. Rev. Cancer 9, 489–499 (2009).
Tian, S. et al. A robust genomic signature for the detection of colorectal cancer patients with microsatellite instability phenotype and high mutation frequency. J. Pathol. 228, 586–595 (2012).
Jorissen, R. N. et al. DNA copy-number alterations underlie gene expression differences between microsatellite stable and unstable colorectal cancers. Clin. Cancer Res. 14, 8061–8069 (2008).
Sinicrope, F. A. et al. DNA mismatch repair status and colon cancer recurrence and survival in clinical trials of 5-fluorouracil-based adjuvant therapy. J. Natl Cancer Inst. 103, 863–875 (2011).
Pogue-Geile, K. et al. Defective mismatch repair and benefit from bevacizumab for colon cancer: findings from NSABP C-08. J. Natl Cancer Inst. 105, 989–992 (2013).
Midgley, R. S. et al. Final results from QUASAR2, a multicenter, international randomized phase III trial of capecitabine +/− bevacizumab in the adjuvant setting of stage II/III colorectal cancer [abstract]. ESMO 2014 Congress LBA12 (2014).
Barault, L. et al. Hypermethylator phenotype in sporadic colon cancer: study on a population-based series of 582 cases. Cancer Res. 68, 8541–8546 (2008).
Domingo, E. et al. BRAF screening as a low-cost effective strategy for simplifying HNPCC genetic testing. J. Med. Genet. 41, 664–668 (2004).
Samowitz, W. S. et al. Poor survival associated with the BRAF V600E mutation in microsatellite-stable colon cancers. Cancer Res. 65, 6063–6069 (2005).
Roth, A. D. et al. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60–00 trial. J. Clin. Oncol. 28, 466–474 (2010).
Lochhead, P. et al. Microsatellite instability and BRAF mutation testing in colorectal cancer prognostication. J. Natl Cancer Inst. 105, 1151–1156 (2013).
Blons, H. et al. Prognostic value of KRAS mutations in stage III colon cancer: post hoc analysis of the PETACC8 phase III trial dataset. Ann. Oncol. 25, 2378–2385 (2014).
Taieb, J. et al. Prognostic value of BRAF V600E and KRAS exon 2 mutations in microsatellite stable (MSS), stage III colon cancers (CC) from patients (pts) treated with adjuvant FOLFOX+/− cetuximab: a pooled analysis of 3934 pts from the PETACC8 and N0147 trials. J. Clin. Oncol. 33 (Suppl.), 3507 (2015).
Pereira, A. A. et al. Association between KRAS mutation and lung metastasis in advanced colorectal cancer. Br. J. Cancer 112, 424–428 (2015).
Dalerba, P. et al. CDX2 as a prognostic biomarker in stage II and stage III colon cancer. N. Engl. J. Med. 374, 211–222 (2016).
Medema, J. P. & Vermeulen, L. Microenvironmental regulation of stem cells in intestinal homeostasis and cancer. Nature 474, 318–326 (2011).
Wang, X., Markowetz, F., De Sousa, E. M. F., Medema, J. P. & Vermeulen, L. Dissecting cancer heterogeneity — an unsupervised classification approach. Int. J. Biochem. Cell Biol. 45, 2574–2579 (2013).
Clark-Langone, K. M. et al. Biomarker discovery for colon cancer using a 761 gene RT-PCR assay. BMC Genomics 8, 279 (2007).
O'Connell, M. J. et al. Relationship between tumor gene expression and recurrence in four independent studies of patients with stage II/III colon cancer treated with surgery alone or surgery plus adjuvant fluorouracil plus leucovorin. J. Clin. Oncol. 28, 3937–3944 (2010).
Salazar, R. et al. Gene expression signature to improve prognosis prediction of stage II and III colorectal cancer. J. Clin. Oncol. 29, 17–24 (2011).
Maak, M. et al. Independent validation of a prognostic genomic signature (ColoPrint) for patients with stage II colon cancer. Ann. Surg. 257, 1053–1058 (2013).
Kuebler, J. P. et al. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J. Clin. Oncol. 25, 2198–2204 (2007).
Yothers, G. et al. Validation of the 12-gene colon cancer recurrence score in NSABP C-07 as a predictor of recurrence in patients with stage II and III colon cancer treated with fluorouracil and leucovorin (FU/LV) and FU/LV plus oxaliplatin. J. Clin. Oncol. 31, 4512–4519 (2013).
Salazar, R. et al. The PARSC trial, a prospective study for the assessment of recurrence risk in stage II colon cancer (CC) patients using ColoPrint [abstract]. J. Clin. Oncol. 29 (Suppl.), TPS167 (2011).
Sadanandam, A. et al. A colorectal cancer classification system that associates cellular phenotype and responses to therapy. Nat. Med. 19, 619–625 (2013).
Budinska, E. et al. Gene expression patterns unveil a new level of molecular heterogeneity in colorectal cancer. J. Pathol. 231, 63–76 (2013).
Marisa, L. et al. Gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value. PLoS Med. 10, e1001453 (2013).
Schlicker, A. et al. Subtypes of primary colorectal tumors correlate with response to targeted treatment in colorectal cell lines. BMC Med. Genomics 5, 66 (2012).
Oh, S. C. et al. Prognostic gene expression signature associated with two molecularly distinct subtypes of colorectal cancer. Gut 61, 1291–1298 (2012).
Roepman, P. et al. Colorectal cancer intrinsic subtypes predict chemotherapy benefit, deficient mismatch repair and epithelial-to-mesenchymal transition. Int. J. Cancer 134, 552–562 (2014).
Sadanandam, A. et al. Reconciliation of classification systems defining molecular subtypes of colorectal cancer: interrelationships and clinical implications. Cell Cycle 13, 353–357 (2014).
Guinney, J. et al. The consensus molecular subtypes of colorectal cancer. Nat. Med. 21, 1350–1356 (2015).
Linnekamp, J. F., Wang, X., Medema, J. P. & Vermeulen, L. Colorectal cancer heterogeneity and targeted therapy: a case for molecular disease subtypes. Cancer Res. 75, 245–249 (2015).
Renfro, L. A. et al. Body mass index is prognostic in metastatic colorectal cancer: pooled analysis of patients from first-line clinical trials in the ARCAD database. J. Clin. Oncol. 34, 144–150 (2016).
Venderbosch, S. et al. Prognostic value of resection of primary tumor in patients with stage IV colorectal cancer: retrospective analysis of two randomized studies and a review of the literature. Ann. Surg. Oncol. 18, 3252–3260 (2011).
't Lam-Boer, J. et al. The CAIRO4 study: the role of surgery of the primary tumour with few or absent symptoms in patients with synchronous unresectable metastases of colorectal cancer — a randomized phase III study of the Dutch Colorectal Cancer Group (DCCG). BMC Cancer 14, 741 (2014).
Rahbari, N. N. et al. Resection of the primary tumour versus no resection prior to systemic therapy in patients with colon cancer and synchronous unresectable metastases (UICC stage IV): SYNCHRONOUS — a randomised controlled multicentre trial (ISRCTN30964555). BMC Cancer 12, 142 (2012).
Kim, C. W. et al. The role of primary tumor resection in colorectal cancer patients with asymptomatic, synchronous unresectable metastasis: study protocol for a randomized controlled trial. Trials 17, 34 (2016).
Cremolini, C. et al. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study. Lancet Oncol. 16, 1306–1315 (2015).
Koopman, M., Venderbosch, S., Nagtegaal, I. D., van Krieken, J. H. & Punt, C. J. A review on the use of molecular markers of cytotoxic therapy for colorectal cancer, what have we learned? Eur. J. Cancer 45, 1935–1949 (2009).
Custodio, A. et al. Molecular markers to predict outcome to antiangiogenic therapies in colorectal cancer: current evidence and future perspectives. Cancer Treat. Rev. 39, 908–924 (2013).
Lenz, H. J. et al. MAVERICC, a phase 2 study of mFOLFOX6-bevacizumab (BV) versus FOLFIRI-BV with biomarker stratification as first-line (1L) chemotherapy (CT) in patients (pts) with metastatic colorectal cancer (mCRC) [abstract]. J. Clin. Oncol. 34 (Suppl. 4S), 493 (2016)..
Li, P. et al. ERCC1, defective mismatch repair status as predictive biomarkers of survival for stage III colon cancer patients receiving oxaliplatin-based adjuvant chemotherapy. Br. J. Cancer 108, 1238–1244 (2013).
Bohanes, P., Labonte, M. J. & Lenz, H. J. A review of excision repair cross-complementation group 1 in colorectal cancer. Clin. Colorectal Cancer 10, 157–164 (2011).
Tabernero, J. et al. Analysis of circulating DNA and protein biomarkers to predict the clinical activity of regorafenib and assess prognosis in patients with metastatic colorectal cancer: a retrospective, exploratory analysis of the CORRECT trial. Lancet Oncol. 16, 937–948 (2015).
Van Cutsem, E. et al. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J. Clin. Oncol. 33, 692–700 (2015).
Peeters, M. et al. Analysis of KRAS/NRAS mutations in a phase III study of panitumumab with FOLFIRI compared with FOLFIRI alone as second-line treatment for metastatic colorectal cancer. Clin. Cancer Res. 21, 5469–5479 (2015).
Douillard, J. Y. et al. Panitumumab–FOLFOX4 treatment and RAS mutations in colorectal cancer. N. Engl. J. Med. 369, 1023–1034 (2013).
Tol, J., Nagtegaal, I. D. & Punt, C. J. BRAF mutation in metastatic colorectal cancer. N. Engl. J. Med. 361, 98–99 (2009).
Rowland, A. et al. Meta-analysis of BRAF mutation as a predictive biomarker of benefit from anti-EGFR monoclonal antibody therapy for RAS wild-type metastatic colorectal cancer. Br. J. Cancer 112, 1888–1894 (2015).
Pietrantonio, F. et al. Predictive role of BRAF mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab: a meta-analysis. Eur. J. Cancer 51, 587–594 (2015).
Bertotti, A. et al. The genomic landscape of response to EGFR blockade in colorectal cancer. Nature 526, 263–267 (2015).
Jhawer, M. et al. PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab. Cancer Res. 68, 1953–1961 (2008).
Sartore-Bianchi, A. et al. PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res. 69, 1851–1857 (2009).
Montagut, C. et al. Identification of a mutation in the extracellular domain of the epidermal growth factor receptor conferring cetuximab resistance in colorectal cancer. Nat. Med. 18, 221–223 (2012).
Misale, S., Di Nicolantonio, F., Sartore-Bianchi, A., Siena, S. & Bardelli, A. Resistance to anti-EGFR therapy in colorectal cancer: from heterogeneity to convergent evolution. Cancer Discov. 4, 1269–1280 (2014).
Bertotti, A. et al. A molecularly annotated platform of patient-derived xenografts (“xenopatients”) identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer. Cancer Discov. 1, 508–523 (2011).
Sartore-Bianchi, A. et al. Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial. Lancet Oncol. 17, 738–746 (2016).
Spindler, K. L., Pallisgaard, N., Andersen, R. F., Brandslund, I. & Jakobsen, A. Circulating free DNA as biomarker and source for mutation detection in metastatic colorectal cancer. PLoS ONE 10, e0108247 (2015).
Misale, S. et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature 486, 532–536 (2012).
Infante, J. R. et al. Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. Lancet Oncol. 13, 773–781 (2012).
Kopetz, S. et al. Phase II pilot study of vemurafenib in patients with metastatic BRAF-mutated colorectal cancer. J. Clin. Oncol. 33, 4032–4038 (2015).
Prahallad, A. et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 483, 100–103 (2012).
Corcoran, R. B. et al. EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov. 2, 227–235 (2012).
Corcoran, R. B. et al. Combined BRAF and MEK inhibition with dabrafenib and trametinib in BRAF V600-mutant colorectal cancer. J. Clin. Oncol. 33, 4023–4031 (2015).
Geel, R. V. et al. Phase I study of the selective BRAFV600inhibitor encorafenib (LGX818) combined with cetuximab and with or without the α-specific PI3K inhibitor BYL719 in patients with advanced BRAF-mutant colorectal cancer [abstract]. J. Clin. Oncol. 32 (Suppl.), 3514 (2014).
Yaeger, R. et al. Pilot trial of combined BRAF and EGFR inhibition in BRAF-mutant metastatic colorectal cancer patients. Clin. Cancer Res. 21, 1313–1320 (2015).
Elez, E. et al. Results of a phase 1b study of the selective BRAF V600 inhibitor encorafenib in combination with cetuximab alone or cetuximab + alpelisib for treatment of patients with advanced BRAF-mutant metastatic colorectal cancer [abstract LBA-08]. Ann. Oncol. 26 (Suppl. 4), iv120 (2015).
Van Cutsem, E. et al. Updated results of the MEK inhibitor trametinib (T), BRAF inhibitor dabrafenib (D), and anti-EGFR antibody panitumumab (P) in patients (pts) with BRAF V600E mutated (BRAFm) metastatic colorectal cancer (mCRC) [abstract LBA-07]. Ann. Oncol. 26 (Suppl. 4), iv119 (2015).
Vecchione, L. et al. A vulnerability of a subset of colon cancers with potential clinical utility. Cell 165, 317–330 (2016).
Le, D. T. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015).
Koopman, M. et al. Deficient mismatch repair system in patients with sporadic advanced colorectal cancer. Br. J. Cancer 100, 266–273 (2009).
Venderbosch, S. et al. Mismatch repair status and BRAF mutation status in metastatic colorectal cancer patients: a pooled analysis of the CAIRO, CAIRO2, COIN, and FOCUS studies. Clin. Cancer Res. 20, 5322–5330 (2014).
Giannakis, M. et al. Genomic correlates of immune-cell infiltrates in colorectal carcinoma. Cell Rep. 15, 857–865 (2016).
Lau, T. et al. A novel tankyrase small-molecule inhibitor suppresses APC mutation-driven colorectal tumor growth. Cancer Res. 73, 3132–3144 (2013).
Waaler, J. et al. A novel tankyrase inhibitor decreases canonical Wnt signaling in colon carcinoma cells and reduces tumor growth in conditional APC mutant mice. Cancer Res. 72, 2822–2832 (2012).
Arques, O. et al. Tankyrase inhibition blocks Wnt/β-catenin pathway and reverts resistance to PI3K and AKT inhibitors in the treatment of colorectal cancer. Clin. Cancer Res. 22, 644–656 (2016).
Liu, J. et al. Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974. Proc. Natl Acad. Sci. USA 110, 20224–20229 (2013).
Proffitt, K. D. et al. Pharmacological inhibition of the Wnt acyltransferase PORCN prevents growth of WNT-driven mammary cancer. Cancer Res. 73, 502–507 (2013).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01351103, (2016).
Madan, B. et al. Wnt addiction of genetically defined cancers reversed by PORCN inhibition. Oncogene 35, 2197–2207 (2016).
Seshagiri, S. et al. Recurrent R-spondin fusions in colon cancer. Nature 488, 660–664 (2012).
Shinmura, K. et al. RSPO fusion transcripts in colorectal cancer in Japanese population. Mol. Biol. Rep. 41, 5375–5384 (2014).
Koo, B. K., van Es, J. H., van den Born, M. & Clevers, H. Porcupine inhibitor suppresses paracrine Wnt-driven growth of Rnf43;Znrf3-mutant neoplasia. Proc. Natl Acad. Sci. USA 112, 7548–7550 (2015).
Storm, E. E. et al. Targeting PTPRK–RSPO3 colon tumours promotes differentiation and loss of stem-cell function. Nature 529, 97–100 (2016).
Do, K. et al. Biomarker-driven phase 2 study of MK-2206 and selumetinib (AZD6244, ARRY-142886) in patients with colorectal cancer. Invest. New Drugs 33, 720–728 (2015).
Zimmer, L. et al. Phase I expansion and pharmacodynamic study of the oral MEK inhibitor RO4987655 (CH4987655) in selected patients with advanced cancer with RAS–RAF mutations. Clin. Cancer Res. 20, 4251–4261 (2014).
Relton, C., Torgerson, D., O'Cathain, A. & Nicholl, J. Rethinking pragmatic randomised controlled trials: introducing the “cohort multiple randomised controlled trial” design. BMJ 340, c1066 (2010).
Burbach, J. P. et al. RandomizEd controlled trial for pre-operAtive dose-escaLation BOOST in locally advanced rectal cancer (RECTAL BOOST study): study protocol for a randomized controlled trial. Trials 16, 58 (2015).
De Sousa, E. M. F., Vermeulen, L., Fessler, E. & Medema, J. P. Cancer heterogeneity — a multifaceted view. EMBO Rep. 14, 686–695 (2013).
Vermeulen, L., de Sousa e Melo, F., Richel, D. J. & Medema, J. P. The developing cancer stem-cell model: clinical challenges and opportunities. Lancet Oncol. 13, e83–e89 (2012).
McGranahan, N. et al. Clonal status of actionable driver events and the timing of mutational processes in cancer evolution. Sci. Transl. Med. 7, 283ra54 (2015).
Sottoriva, A. et al. A Big Bang model of human colorectal tumor growth. Nat. Genet. 47, 209–216 (2015).
Normanno, N. et al. Heterogeneity of KRAS, NRAS, BRAF and PIK3CA mutations in metastatic colorectal cancer and potential effects on therapy in the CAPRI GOIM trial. Ann. Oncol. 26, 1710–1714 (2015).
Ciardiello, F. et al. Clinical activity of FOLFIRI plus cetuximab according to extended gene mutation status by next-generation sequencing: findings from the CAPRI-GOIM trial. Ann. Oncol. 25, 1756–1761 (2014).
Molinari, F. et al. Increased detection sensitivity for KRAS mutations enhances the prediction of anti-EGFR monoclonal antibody resistance in metastatic colorectal cancer. Clin. Cancer Res. 17, 4901–4914 (2011).
Laurent-Puig, P. et al. Clinical relevance of KRAS-mutated subclones detected with picodroplet digital PCR in advanced colorectal cancer treated with anti-EGFR therapy. Clin. Cancer Res. 21, 1087–1097 (2015).
Diaz, L. A. Jr et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature 486, 537–540 (2012).
Enriquez-Navas, P. M., Wojtkowiak, J. W. & Gatenby, R. A. Application of evolutionary principles to cancer therapy. Cancer Res. 75, 4675–4680 (2015).
Gatenby, R. A., Silva, A. S., Gillies, R. J. & Frieden, B. R. Adaptive therapy. Cancer Res. 69, 4894–4903 (2009).
Enriquez-Navas, P. M. et al. Exploiting evolutionary principles to prolong tumor control in preclinical models of breast cancer. Sci. Transl. Med. 8, 327ra24 (2016).
Zhao, B. et al. Exploiting temporal collateral sensitivity in tumor clonal evolution. Cell 165, 234–246 (2016).
Dalerba, P. et al. Phenotypic characterization of human colorectal cancer stem cells. Proc. Natl Acad. Sci. USA 104, 10158–10163 (2007).
O'Brien, C. A., Pollett, A., Gallinger, S. & Dick, J. E. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445, 106–110 (2007).
Huang, E. H. et al. Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis. Cancer Res. 69, 3382–3389 (2009).
Ricci-Vitiani, L. et al. Identification and expansion of human colon-cancer-initiating cells. Nature 445, 111–115 (2007).
Vermeulen, L. et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat. Cell Biol. 12, 468–476 (2010).
Vermeulen, L. et al. Single-cell cloning of colon cancer stem cells reveals a multi-lineage differentiation capacity. Proc. Natl Acad. Sci. USA 105, 13427–13432 (2008).
Fan, C. W. et al. Cancer-initiating cells derived from human rectal adenocarcinoma tissues carry mesenchymal phenotypes and resist drug therapies. Cell Death Dis. 4, e828 (2013).
Zeuner, A., Todaro, M., Stassi, G. & De Maria, R. Colorectal cancer stem cells: from the crypt to the clinic. Cell Stem Cell 15, 692–705 (2014).
Dylla, S. J. et al. Colorectal cancer stem cells are enriched in xenogeneic tumors following chemotherapy. PLoS ONE 3, e2428 (2008).
Todaro, M. et al. Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4. Cell Stem Cell 1, 389–402 (2007).
Colak, S. et al. Decreased mitochondrial priming determines chemoresistance of colon cancer stem cells. Cell Death Differ. 21, 1170–1177 (2014).
Colak, S. & Medema, J. P. Human colonic fibroblasts regulate stemness and chemotherapy resistance of colon cancer stem cells. Cell Cycle 15, 1531–1537 (2014).
Borovski, T., De Sousa, E. M. F., Vermeulen, L. & Medema, J. P. Cancer stem cell niche: the place to be. Cancer Res. 71, 634–639 (2011).
Luraghi, P. et al. MET signaling in colon cancer stem-like cells blunts the therapeutic response to EGFR inhibitors. Cancer Res. 74, 1857–1869 (2014).
Todaro, M. et al. CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis. Cell Stem Cell 14, 342–356 (2014).
Lotti, F. et al. Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A. J. Exp. Med. 210, 2851–2872 (2013).
Barretina, J. et al. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 483, 603–607 (2012).
Garnett, M. J. et al. Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature 483, 570–575 (2012).
van de Wetering, M. et al. Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell 161, 933–945 (2015).
Julien, S. et al. Characterization of a large panel of patient-derived tumor xenografts representing the clinical heterogeneity of human colorectal cancer. Clin. Cancer Res. 18, 5314–5328 (2012).
Uronis, J. M. et al. Histological and molecular evaluation of patient-derived colorectal cancer explants. PLoS ONE 7, e38422 (2012).
Weeber, F. et al. Preserved genetic diversity in organoids cultured from biopsies of human colorectal cancer metastases. Proc. Natl Acad. Sci. USA 112, 13308–13311 (2015).
L.V. is supported by KWF grants (UVA2011-4969 and UVA2014-7245), a Worldwide Cancer Research grant (14–1164), a Maag Lever Darm Stichting grant (MLDS-CDG 14–03), the European Research Council (ERG-StG 638193), and a NWO Vidi grant (917.15.308).
C.J.A.P. has an advisory role for Servier and Nordic Pharma. M.K. has an advisory role for Servier. L.V. declares no competing interests.
About this article
Cite this article
Punt, C., Koopman, M. & Vermeulen, L. From tumour heterogeneity to advances in precision treatment of colorectal cancer. Nat Rev Clin Oncol 14, 235–246 (2017). https://doi.org/10.1038/nrclinonc.2016.171
Identification of genes with high heterogeneity of expression as a predictor of different prognosis and therapeutic responses in colorectal cancer: a challenge and a strategy
Cancer Cell International (2022)
Construction and validation of a novel prognostic model for lung squamous cell cancer based on N6-methyladenosine-related genes
World Journal of Surgical Oncology (2022)
World Journal of Surgical Oncology (2022)
xCT contributes to colorectal cancer tumorigenesis through upregulation of the MELK oncogene and activation of the AKT/mTOR cascade
Cell Death & Disease (2022)
An analysis of the significance of the Tre2/Bub2/CDC 16 (TBC) domain protein family 8 in colorectal cancer
Scientific Reports (2022)