Personalizing Therapy for Colorectal Cancer
2013; Elsevier BV; Volume: 12; Issue: 1 Linguagem: Inglês
10.1016/j.cgh.2013.08.040
ISSN1542-7714
Autores Tópico(s)Cancer Genomics and Diagnostics
ResumoColorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide. Several important scientific discoveries in the molecular biology of CRC have changed clinical practice in oncology. These included the comprehensive genome-wide profiling of CRC by the Cancer Genome Atlas Network, the discovery of mutations along the RAS-RAF signaling pathway as major determinants of response to antibodies against the epidermal growth factor receptor, the elucidation of new molecular subsets of CRC or gene signatures that may predict clinical outcome after adjuvant chemotherapy, and the innovative targeting of the family of vascular endothelial growth factor and receptors. These new data have allowed oncologists to individualize drug therapy on the basis of a patient's tumor's unique molecular profile, especially in the management of metastatic CRC. This review article will discuss the progress of personalized medicine in the contemporary management of CRC. Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide. Several important scientific discoveries in the molecular biology of CRC have changed clinical practice in oncology. These included the comprehensive genome-wide profiling of CRC by the Cancer Genome Atlas Network, the discovery of mutations along the RAS-RAF signaling pathway as major determinants of response to antibodies against the epidermal growth factor receptor, the elucidation of new molecular subsets of CRC or gene signatures that may predict clinical outcome after adjuvant chemotherapy, and the innovative targeting of the family of vascular endothelial growth factor and receptors. These new data have allowed oncologists to individualize drug therapy on the basis of a patient's tumor's unique molecular profile, especially in the management of metastatic CRC. This review article will discuss the progress of personalized medicine in the contemporary management of CRC. Colorectal cancer (CRC) is the third most commonly diagnosed cancer in both men and women worldwide.1Jemal A. Bray F. Center M.M. et al.Global cancer statistics.CA Cancer J Clin. 2011; 61: 69-90Crossref PubMed Scopus (29831) Google Scholar The last decade has witnessed some important scientific discoveries in the molecular biology of CRC that have resulted in dramatic shifts in the treatment paradigms for metastatic CRC. These included the comprehensive genome-wide profiling of CRC by the Cancer Genome Atlas Network,2Cancer Genome Atlas NetworkComprehensive molecular characterization of human colon and rectal cancer.Nature. 2012; 487: 330-337Crossref PubMed Scopus (5622) Google Scholar the discovery of mutations along the RAS-RAF signaling pathway as major determinants of response to antibodies against the epidermal growth factor receptor (EGFR), the elucidation of new molecular subsets of CRC that may predict clinical outcome after adjuvant chemotherapy,3Simon I. Roepman P. Schlicker A. et al.Association of colorectal cancer intrinsic subtypes with prognosis, chemotherapy response, deficient mismatch repair, and epithelial to mesenchymal transition (EMT): Proc ASCO GI meeting.J Clin Oncol. 2013; (abstr 333)Google Scholar, 4Kelley R.K. Venook A.P. Prognostic and predictive markers in stage II colon cancer: is there a role for gene expression profiling?.Clin Colorectal Cancer. 2011; 10: 73-80Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar and the innovative targeting of the family of vascular endothelial growth factor (VEGF) and receptors (VEGFRs). This body of knowledge has not just enabled us to individualize drug treatment on the basis of molecular profiles; they have contributed to the improvement of prognosis in advanced CRC. The latter has been achieved through the development of new targeted therapies and by changing the way we manage patients with oligometastases from CRC. This review article will discuss the progress of personalized medicine in the contemporary management of CRC. The concept of individualized drug therapy in CRC is not new, and traditional factors such as a patient's performance status, presence of medical comorbidities, TNM staging, and specific histopathologic characteristics still heavily influence the decision-making process of oncologists. However, this approach is limited because it does not adequately explain the differential response to drug therapy in individuals; furthermore, it may inadvertently result in the overtreatment of patients. The latter is exemplified by the adjuvant treatment of stage II CRC, where the number of patients needed to be treated with adjuvant chemotherapy to prevent 1 recurrence or death is 25–50 patients, at the expense of 1 in 6 patients experiencing serious toxicity.5Kopetz S. Freitas D. Calabrich A.F. et al.Adjuvant chemotherapy for stage II colon cancer.Oncology (Williston Park). 2008; 22: 260-270PubMed Google Scholar Genome-wide molecular profiling studies have shown that CRC is a heterogeneous disease characterized by multiple genetic and epigenetic alterations. Molecular changes such as microsatellite instability (MSI), CpG island methylator phenotype (CIMP), global DNA hypomethylation, and chromosomal instability that result in the activation of oncogenic pathways are commonly found in most CRC tumors.6Ogino S. Chan A.T. Fuchs C.S. et al.Molecular pathological epidemiology of colorectal neoplasia: an emerging transdisciplinary and interdisciplinary field.Gut. 2010; 60: 397-411Crossref PubMed Scopus (414) Google Scholar The reader should refer to some excellent reviews on the molecular pathogenesis of CRC, because a detailed discussion on this topic is beyond the scope of this review.6Ogino S. Chan A.T. Fuchs C.S. et al.Molecular pathological epidemiology of colorectal neoplasia: an emerging transdisciplinary and interdisciplinary field.Gut. 2010; 60: 397-411Crossref PubMed Scopus (414) Google Scholar, 7van Engeland M. Derks S. Smits K.M. et al.Colorectal cancer epigenetics: complex simplicity.J Clin Oncol. 2011; 29: 1382-1391Crossref PubMed Scopus (170) Google Scholar, 8Yamauchi M. Morikawa T. Kuchiba A. et al.Assessment of colorectal cancer molecular features along bowel subsites challenges the conception of distinct dichotomy of proximal versus distal colorectum.Gut. 2012; 61: 847-854Crossref PubMed Scopus (449) Google Scholar, 9Soreide K. Nedrebo B.S. Knapp J.C. et al.Evolving molecular classification by genomic and proteomic biomarkers in colorectal cancer: potential implications for the surgical oncologist.Surg Oncol. 2009; 18: 31-50Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar Recently, the landmark publication by the Cancer Genome Atlas Network on CRC has reported new driver mutations and provided a unifying view of the known genetic and epigenetic aberrations.2Cancer Genome Atlas NetworkComprehensive molecular characterization of human colon and rectal cancer.Nature. 2012; 487: 330-337Crossref PubMed Scopus (5622) Google Scholar This seminal work has shown that colon and rectal cancers are similar on a genomic level, whereas proximally located primary tumors are more likely to exhibit a "hypermutated" genomic profile than distally located tumors. This profile consists of much higher frequencies of somatic mutations, microsatellite unstable status, mismatch repair gene mutation, and CIMP. Apart from confirming that genetic alterations are common in the Wingless (Wnt), phosphoinositide 3-kinase (PI3K)-AKT, RAS-RAF-ERK, and transforming growth factor receptor-beta signaling pathways, newer aberrations such as amplification of HER2 and insulin-like growth factor 2 and somatic mutations of AT-rich interactive domain-containing protein 1A, sex determining region Y-box 9, and family with sequence similarity 123B may represent potential biomarker or therapeutic targets.2Cancer Genome Atlas NetworkComprehensive molecular characterization of human colon and rectal cancer.Nature. 2012; 487: 330-337Crossref PubMed Scopus (5622) Google Scholar In the following sections, the translational significance of these basic scientific discoveries will be presented in 2 clinical settings, metastatic and adjuvant. Cetuximab and panitumumab are monoclonal antibodies targeting the extracellular domain of the EGFR and have been used in clinics for more than a decade. Historically, these drugs were once administered in unselected patient population, with modest gains in response rate and progression-free survival (PFS).10Van Cutsem E. Kohne C.H. Hitre E. et al.Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer.N Engl J Med. 2009; 360: 1408-1417Crossref PubMed Scopus (3185) Google Scholar, 11Douillard J.Y. Siena S. Cassidy J. 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. 2010; 28: 4697-4705Crossref PubMed Scopus (1454) Google Scholar, 12Jonker D.J. O'Callaghan C.J. Karapetis C.S. et al.Cetuximab for the treatment of colorectal cancer.N Engl J Med. 2007; 357: 2040-2048Crossref PubMed Scopus (1662) Google Scholar, 13Van Cutsem E. Peeters M. Siena S. et al.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; 25: 1658-1664Crossref PubMed Scopus (1693) Google Scholar, 14Sobrero A.F. Maurel J. Fehrenbacher L. et al.EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer.J Clin Oncol. 2008; 26: 2311-2319Crossref PubMed Scopus (806) Google Scholar, 15Peeters M. Price T.J. Cervantes A. et al.Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer.J Clin Oncol. 2010; 28: 4706-4713Crossref PubMed Scopus (792) Google Scholar The RAS-RAF signaling is one of the effector pathways located downstream to the EGFR, which also cross-talk with the PI3K-AKT pathway. Activating mutations of KRAS, BRAF, and PIK3CA have been implicated as escape mechanisms that can bypass the growth inhibitory effect of EGFR blockade.16Bardelli A. Siena S. Molecular mechanisms of resistance to cetuximab and panitumumab in colorectal cancer.J Clin Oncol. 2010; 28: 1254-1261Crossref PubMed Scopus (555) Google Scholar KRAS mutations can be found in around 40% of CRC, of which around 90% occur at codon 12 or 13.16Bardelli A. Siena S. Molecular mechanisms of resistance to cetuximab and panitumumab in colorectal cancer.J Clin Oncol. 2010; 28: 1254-1261Crossref PubMed Scopus (555) Google Scholar Since mid-2005, data began to emerge on the strong association between KRAS mutation and resistance to EGFR antibodies in retrospective series and post hoc analyses of phase III studies (Figure 1).17Amado R.G. Wolf M. Peeters M. et al.Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer.J Clin Oncol. 2008; 26: 1626-1634Crossref PubMed Scopus (2733) Google Scholar, 18Lievre A. Bachet J.B. Le Corre D. et al.KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer.Cancer Res. 2006; 66: 3992-3995Crossref PubMed Scopus (1874) Google Scholar, 19Di Fiore F. Blanchard F. Charbonnier F. et al.Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by cetuximab plus chemotherapy.Br J Cancer. 2007; 96: 1166-1169Crossref PubMed Scopus (669) Google Scholar Collectively, these studies have shown that patients with KRAS mutant cancers do not derive any added benefit in terms of tumor control and survival when being treated with EGFR antibodies alone or in combination with chemotherapy, perhaps with the exception of some patients with the relatively uncommon G13D mutation.20De Roock W. De Vriendt V. Normanno N. et al.KRAS, BRAF, PIK3CA, and PTEN mutations: implications for targeted therapies in metastatic colorectal cancer.Lancet Oncol. 2011; 12: 594-603Abstract Full Text Full Text PDF PubMed Scopus (456) Google Scholar The drug insert for cetuximab and panitumumab has since been revised, recommending mandatory testing for KRAS mutation before starting therapy. To cite an example of the powerful predictive effect of KRAS mutation on clinical response to anti-EGFR antibodies, the phase III CRYSTAL study was a pivotal study that led to the approval of cetuximab in combination with chemotherapy in the first-line treatment of metastatic CRC.10Van Cutsem E. Kohne C.H. Hitre E. et al.Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer.N Engl J Med. 2009; 360: 1408-1417Crossref PubMed Scopus (3185) Google Scholar The hazard ratio (HR) for the primary end point of PFS among patients treated with cetuximab plus chemotherapy who had tumors with wild-type KRAS was 0.68 (P = .02), compared with those with KRAS-mutant tumors, HR = 1.07 (P = .75). Patients with KRAS wild-type tumors also had a higher response rate of 59.3% than those with KRAS-mutant tumors (36.2%) after treatment with cetuximab chemotherapy.10Van Cutsem E. Kohne C.H. Hitre E. et al.Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer.N Engl J Med. 2009; 360: 1408-1417Crossref PubMed Scopus (3185) Google Scholar Besides KRAS mutation, accumulating evidence suggests that mutations in other downstream components of EGFR pathway affecting the BRAF, PIK3CA, NRAS, and PTEN genes have also been associated with poor prognosis after treatment with anti-EGFR antibodies in metastatic CRC.21Price T.J. Hardingham J.E. Lee C.K. et al.Impact of KRAS and BRAF gene mutation status on outcomes from the phase III AGITG MAX trial of capecitabine alone or in combination with bevacizumab and mitomycin in advanced colorectal cancer.J Clin Oncol. 2011; 29: 2675-2682Crossref PubMed Scopus (170) Google Scholar, 22De 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. 2011; 11: 753-762Abstract Full Text Full Text PDF Scopus (1659) Google Scholar, 23Van Cutsem E. Dicato M. Arber N. et al.Molecular markers and biological targeted therapies in metastatic colorectal cancer: expert opinion and recommendations derived from the 11th ESMO/World Congress on Gastrointestinal Cancer, Barcelona, 2009.Ann Oncol. 2010; 21: vi1-vi10Crossref PubMed Scopus (37) Google Scholar However, clinical application of these biomarkers is limited by their relatively low level of expression in CRC. To date, no oncological guidelines have recommended routine testing for these markers in metastatic CRC. Cancer pharmacogenomics is also another area that has been extensively investigated in CRC. Certain genotypic variants such as those affecting the genes encoding the UDP-glucuronosyltransferase 1A1 enzyme (which is involved in the metabolism of irinotecan) and dihydropyrimidine dehydrogenase (involved in the metabolism of 5-fluorouracil [5-FU]) are now available for clinical testing. However, the cause of an individual's susceptibility to drug toxicity is usually multifactorial involving multiple genetic as well as non-genetic (eg, drug scheduling) factors. For instance, the UGT1A1 polymorphism is not as predictive of severe toxicity to irinotecan in patients receiving the more popularly used, 2-weekly schedule of irinotecan than the less commonly used 3-weekly schedule.24Stewart C.F. Panetta J.C. O'Shaughnessy M.A. et al.UGT1A1 promoter genotype correlates with SN-38 pharmacokinetics, but not severe toxicity in patients receiving low-dose irinotecan.J Clin Oncol. 2007; 25: 2594-2600Crossref PubMed Scopus (77) Google Scholar Common polymorphisms in genes encoding for other proteins such as adenosine triphosphate binding cassette and solute carrier transporters may also contribute to increased vulnerability to irinotecan toxicity.25Innocenti F. Kroetz D.L. Schuetz E. et al.Comprehensive pharmacogenetic analysis of irinotecan neutropenia and pharmacokinetics.J Clin Oncol. 2009; 27: 2604-2614Crossref PubMed Scopus (209) Google Scholar Therefore, the clinical impact and applicability of these tests remain controversial and are not in routine use in Hong Kong and most Asian centers.26Kelley R.K. Van Bebber S.L. Phillips K.A. et al.Personalized medicine and oncology practice guidelines: a case study of contemporary biomarkers in colorectal cancer.J Natl Compr Canc Netw. 2011; 9: 13-25PubMed Google Scholar For the management of patients with metastases that are limited to the liver or lung, the aim is to optimize tumor shrinkage with more intensive drug regimens to achieve potentially curative resection. The availability of more effective neoadjuvant drug therapy has dramatically changed the prognosis of patients with initially inoperable or borderline resectable liver metastases. The 5-year survival of patients who presented with inoperable liver metastases is now approaching that of patients who presented with operable tumors, after multimodal treatment with chemotherapy, liver resection, and local ablative therapy.27Adam R. Wicherts D.A. de Haas R.J. et al.Patients with initially unresectable colorectal liver metastases: is there a possibility of cure?.J Clin Oncol. 2009; 27: 1829-1835Crossref PubMed Scopus (434) Google Scholar The addition of targeted therapy such as anti-EGFR antibodies to chemotherapy in patients with KRAS–wild-type liver metastases has further extended tumor response rate to greater than 70%, R0 resection rate of greater than 30%, and also overall survival (OS) compared with chemotherapy alone in a recently published study.28Folprecht G. Gruenberger T. Bechstein W.O. 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: 38-47Abstract Full Text Full Text PDF PubMed Scopus (774) Google Scholar, 29Wong R. Cunningham D. Barbachano Y. et al.A multicentre study of capecitabine, oxaliplatin plus bevacizumab as perioperative treatment of patients with poor-risk colorectal liver-only metastases not selected for upfront resection.Ann Oncol. 2010; 22: 2042-2048Crossref Scopus (169) Google Scholar, 30Ye L.C. Liu T.S. Ren L. et al.Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases.J Clin Oncol. 2013; 31: 1931-1938Crossref PubMed Scopus (293) Google Scholar In a phase III study reported by Ye et al,30Ye L.C. Liu T.S. Ren L. et al.Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases.J Clin Oncol. 2013; 31: 1931-1938Crossref PubMed Scopus (293) Google Scholar patients with KRAS wild-type CRC who were randomized to chemotherapy and cetuximab experienced higher 3-year OS rate (41% vs 18%, P = .013) and median OS (30.9 vs 21.0 months, P = .013), compared with those who received chemotherapy alone. In recognition of the improved prognosis of patients with oligometastases, the latest American Joint Committee on Cancer classification of CRC has divided the M stage into M1a (oligometastases) and M1b (multiple sites of metastases).31Edge S.G. Byrd D.R. Compton C.C. Colon and rectum. 7th ed. Springer, New York2010: 173-260Google Scholar VEGF is the key regulator of angiogenesis that is essential for tumor growth and metastasis in CRC. Bevacizumab is the first anti-angiogenesis drug that has been approved in the treatment of metastatic CRC (and also for any cancer) in 2004.32Hurwitz H.F. Novotny L. Cartwright W. et al.Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer.N Engl J Med. 2004; 350: 2335-2342Crossref PubMed Scopus (9029) Google Scholar Two recently reported phase III studies may have practice-changing implications. The first of these 2 studies is the TML study, which is the first phase III study to show that in patients with progressive metastatic CRC during first-line treatment with bevacizumab and chemotherapy, the continuation of VEGF inhibition with bevacizumab when switching across to subsequent line of chemotherapy will confer added survival benefit. Patients who were continued on bevacizumab on subsequent line of chemotherapy had higher median OS (11.2 months) than those who did not (9.8 months; HR, 0.81; 95% confidence interval [CI], 0.69–0.94; P = .0062), compared with if bevacizumab is discontinued.33Arnold D. Bennouna J. Sastre J. et al.Bevacizumab plus chemotherapy continued beyond first progression in patients with metastatic colorectal cancer previously treated with bevacizumab plus chemotherapy: results of a randomized phase III intergroup study (TML study)—Proc ASCO Annual Meeting.J Clin Oncol. 2012; 30Google Scholar The second study, dubbed the DREAM study, is one of the first reported phase III studies that investigated the use of bevacizumab as a maintenance therapy in combination with erlotinib (an EGFR tyrosine kinase inhibitor), after optimal response to first-line chemotherapy for metastatic CRC.34Tournigand C. Scheithauer W. Lledo G. et al.Bevacizumab (Bev) with or without erlotinib as maintenance therapy, following induction first-line chemotherapy plus Bev, in patients (pts) with metastatic colorectal cancer (mCRC): efficacy and safety results of the International GERCOR DREAM phase III trial—Proc ASCO Annual Meeting.J Clin Oncol. 2012; 30PubMed Google Scholar The DREAM study showed that the bevacizumab-erlotinib arm resulted in a longer median PFS of 5.8 months vs 4.6 months in the bevacizumab alone arm (HR, 0.73; 95% CI, 0.59–0.91; P = .005). Both the TML and DREAM studies enrolled patients who were medically fit and excluded those with rapidly progressive disease or poor response to chemotherapy. Therefore, careful selection of patients for these 2 different treatment strategies is needed in practice. Two new drugs targeting angiogenesis have recently been approved for the treatment of metastatic CRC. Aflibercept is a fully human recombinant fusion protein that consists of the VEGF-binding portions from the extracellular domains of human VEGFR 1 and 2 and the Fc portion of human immunoglobulin G1. It acts as a decoy by binding to the circulating angiogenic factors VEGF-A, VEGF-B, and placental growth factor, so that they cannot bind to the respective receptors.35Van Cutsem E. Tabernero J. Lakomy R. 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. 2013; 30: 3499-3506Crossref Scopus (1000) Google Scholar In the registrational, phase III VELOUR study, the addition of aflibercept to chemotherapy significantly improved OS and PFS in patients receiving second-line chemotherapy. Patients who received aflibercept chemotherapy had better PFS (6.90 vs 4.67 months; HR, 0.75; 95% CI, 0.661–0.869; P <.0001), OS (13.50 vs 12.06 months; HR, 0.817; 95% CI, 0.713–0.937; P = .0032), and response rate (19.8% vs 11.1%) than those who received chemotherapy alone.35Van Cutsem E. Tabernero J. Lakomy R. 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. 2013; 30: 3499-3506Crossref Scopus (1000) Google Scholar It showed a consistent trend of clinical benefit regardless of prior usage of bevacizumab. Regorafenib is another newly approved drug that is an oral multi-kinase inhibitor against VEGFR 1, 2, and 3, BRAF, KIT, RET, platelet-derived growth factor receptor-β, and fibroblast growth factor receptor.36Grothey A. Van Cutsem E. Sobrero A. et al.Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial.Lancet. 2012; 381: 303-312Abstract Full Text Full Text PDF PubMed Scopus (1835) Google Scholar In the registrational, phase III CORRECT study, patients who have progressed despite all standard therapies derived an absolute OS benefit of around 1.4 months with regorafenib when compared with placebo. The median OS was 6.4 months in the regorafenib group vs 5.0 months in the placebo group (HR, 0.77; 95% CI, 0.64–0.94; one-sided P = .0052).36Grothey A. Van Cutsem E. Sobrero A. et al.Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial.Lancet. 2012; 381: 303-312Abstract Full Text Full Text PDF PubMed Scopus (1835) Google Scholar In the subgroup analysis, patients with colon cancer had higher OS (HR, 0.70; 95% CI, 0.56–0.89) than those with rectal cancer (HR, 0.95; 95% CI, 0.63–1.43). To date, a predictive marker of response to regorafenib has not been identified; therefore, additional research is needed on how to optimally select patients for these anti-angiogenesis agents. Many potential biomarkers have been implicated, including plasma angiogenic factors, circulating endothelial cells, and microvessel density; however, none are in clinical use currently. The use of adjuvant chemotherapy in stage III disease is well-proven. Yet, there are still a lot of controversies regarding its use in stage II disease. The widely used clinical factors such as the presence of intestinal obstruction or perforation at presentation and histologic factors such as lymphovascular invasion, poor differentiation, and the number of lymph nodes sampled during surgery do not accurately discriminate patients who will benefit from chemotherapy from those who will not.37Morris E.J. Maughan N.J. Forman D. et al.Who to treat with adjuvant therapy in Dukes B/stage II colorectal cancer? the need for high quality pathology.Gut. 2007; 56: 1419-1425Crossref PubMed Scopus (103) Google Scholar, 38Le Voyer T.E. Sigurdson E.R. Hanlon A.L. et al.Colon cancer survival is associated with increasing number of lymph nodes analyzed: a secondary survey of intergroup trial INT-0089.J Clin Oncol. 2003; 21: 2912-2919Crossref PubMed Scopus (917) Google Scholar Tumoral expression of MSI-high is the only biomarker being used today in some centers for selecting patients for adjuvant 5-FU, which is based on evidence categorized as 2A by the U.S. National Comprehensive Cancer Network guideline.26Kelley R.K. Van Bebber S.L. Phillips K.A. et al.Personalized medicine and oncology practice guidelines: a case study of contemporary biomarkers in colorectal cancer.J Natl Compr Canc Netw. 2011; 9: 13-25PubMed Google Scholar However, the use of MSI as a biomarker does not seem to be universally accepted.23Van Cutsem E. Dicato M. Arber N. et al.Molecular markers and biological targeted therapies in metastatic colorectal cancer: expert opinion and recommendations derived from the 11th ESMO/World Congress on Gastrointestinal Cancer, Barcelona, 2009.Ann Oncol. 2010; 21: vi1-vi10Crossref PubMed Scopus (37) Google Scholar Some recently published large retrospective subgroup or pooled analyses seem to support MSI-high (or mismatch repair deficient, dMMR phenotype) as a predictive marker of lack of benefit from adjuvant 5-FU. These patients have inherently better prognosis than those with MSI-stable or proficient mismatch repair status.39Sargent D.J. Marsoni S. Monges G. et al.Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer.J Clin Oncol. 2010; 28: 3219-3226Crossref PubMed Scopus (1101) Google Scholar, 40Hutchins G. Southward K. Handley K. et al.Value of mismatch repair, KRAS, and BRAF mutations in predicting recurrence and benefits from chemotherapy in colorectal cancer.J Clin Oncol. 2012; 29: 1261-1270Crossref Scopus (501) Google Scholar Recent research has shifted attention to more genomic-based biomarkers. Several microarray-based gene signatures have been validated to date, and some of these are now commercially available. The Oncotype DX gene signature is a 12-gene signature that has been developed from prospective clinical datasets, whereas the ColoPrint gene signature is derived from smaller, retrospective clinical datasets.4Kelley R.K. Venook A.P. Prognostic and predictive markers in stage II colon cancer: is there a role for gene expression profiling?.Clin Colorectal Cancer. 2011; 10: 73-80Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar Both gene signatures classify patients with stage II CRC into either 2 or 3 different prognostic groups, which may be useful in counseling patients with regard to the risk of recurrence after surgery. However, neither signature can predict whether a patient may benefit from adjuvant chemotherapy. A more exciting development on the horizon is the recent report of new molecular classifier of CRC that is based on large-scale, unbiased, genome-wide analysis of 188 tumor samples of stage I–IV CRC.3Simon I. Roepman P. Schlicker A. et al.Association of colorectal cancer intrinsic subtypes with prognosis, chemotherapy response, deficient mismatch repair, and epithelial to mesenchymal transition (EMT): Proc ASCO GI meeting.J Clin Oncol. 2013; (abstr 333)Google Scholar This study divided CRC into subtypes A, B, and C, which differ mainly according to the presence of markers of epithelial-mesenchymal transition, defects in DNA mismatch repair and mutation frequencies, and the rate of proliferation. Patients with subtype C tumors have the worse prognosis and will not benefit from adjuvant chemotherapy, compared with those with other subtypes. The practical application of this new prognostic classifier waits further evaluation.3Simon I. Roepman P. Schlicker A. et al.Association of colorectal cancer intrinsic subtypes with prognosis, chemotherapy response, deficient mismatch repair, and epithelial to mesenchymal transition (EMT): Proc ASCO GI meeting.J Clin Oncol. 2013; (abstr 333)Google Scholar Large strides have been made in the development of personalized drug therapy in the palliative and adjuvant treatment of CRC. The testing of KRAS mutation is now routinely performed in many centers around the world for selecting patients for anti-EGFR antibodies, and the use of MSI status or gene signatures for selecting patients with stage II CRC for adjuvant chemotherapy is gaining increasing popularity (Table 1).26Kelley R.K. Van Bebber S.L. Phillips K.A. et al.Personalized medicine and oncology practice guidelines: a case study of contemporary biomarkers in colorectal cancer.J Natl Compr Canc Netw. 2011; 9: 13-25PubMed Google Scholar There are still hurdles to overcome in the development of personalized drug therapy for CRC, and some of these problems include intratumor heterogeneity in the expression of driver gene mutations,41Gerlinger M. Rowan A.J. Horswell S. et al.Intratumor heterogeneity and branched evolution revealed by multiregion sequencing.N Engl J Med. 2012; 366: 883-892Crossref PubMed Scopus (5532) Google Scholar reproducibility and costs of gene expression profiling platforms, and discordance of biomarker expressions between primary and metastasis. Additional efforts are needed to address these problems.Table 1Highlights of This Review on CRCMetastatic CRC•Activating KRAS mutation is a powerful predictor of treatment response to antibodies against EGFR. It is mandatory to undergo KRAS mutation testing before commencing EGFR antibodies.•In patients with liver-limited metastatic CRCs that are KRAS–wild-type, the addition of EGFR antibodies to neoadjuvant chemotherapy has been associated with better survival and R0 resection rate of the liver metastases in a randomized study.•Mutations of NRAS, BRAF, and PIK3CA have been associated with poor survival after treatment with EGFR antibodies.•Three inhibitors of angiogenesis have now been shown to improve survival in phase III trials. These included an antibody against VEGF, a circulating VEGF-receptor-trap (or decoy), aflibercept, and a VEGF–receptor-tyrosine kinase, regorafenib.•Bevacizumab improves survival when combined with chemotherapy and prolongs PFS when it is continued beyond disease progression after first-line chemotherapy in metastatic colon cancer. It may also improve treatment outcome when used as "maintenance therapy" in combination with erlotinib after an initial response to multi-agent chemotherapy.Adjuvant setting for stage II-III CRC•MSI (or deficiency in mismatch repair) status has been associated with lack of benefit to adjuvant 5-FU.•Some gene signatures may discriminate patient prognosis after adjuvant chemotherapy; however, they do not predict benefit from specific cytotoxic drug. Open table in a new tab
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