June 2013, Vol 2, No 4
Gene Profiling in Colon Cancer: How to Integrate Profiling Into Practice
Dr Van Loon is Assistant Clinical Professor, University of California, San Francisco (UCSF). She is a gastrointestinal cancer specialist, with a particular interest in colon cancer.
Dr Atreya is Adjunct Instructor at UCSF. She is a gastrointestinal oncologist and scientist whose research focuses on the interplay between genotype and response to therapy in advanced colorectal cancer.
Dr Kelley is Assistant Professor at UCSF. She is a gastrointestinal oncologist with a research interest in developing biomarker-
stratified clinical trials to identify new treatments, particularly for hepatocellular and bile duct cancers.
Dr Venook is Professor at UCSF. He is a nationally renowned expert in colorectal and liver cancers at the UCSF Helen Diller Family Comprehensive Cancer Center, where he leads the gastrointestinal oncology program.
The premise behind the “individualization of cancer care” assumes that there are subsets of patients with tumors harboring clinically relevant targets for patient-specific treatments. Currently, very little of the genomic information in colon cancer has clear clinical applicability; however, recent developments raise the prospects for better matching of patients with treatments.
This optimism derives from the sentinel discovery of a strong and discrete predictive biomarker in colon cancer: the association of KRAS mutations with the lack of efficacy of epidermal growth factor receptor (EGFR) antibodies. The importance of KRAS became apparent in 2008 when the first evidence was presented that codon 12 and codon 13 KRAS mutations were predictive of resistance to EGFR monoclonal antibodies in patients with metastatic colon cancer.1
As one would predict, the utilization of EGFR inhibitors subsequently declined as oncologists tailored therapeutic plans to limit exposure to inactive agents for this subset of colon cancer patients.2 It is possible that this knowledge has even resulted in inappropriate underuse of these agents.2 Beyond KRAS, however, the search for predictive biomarkers for colon cancer has been largely unproductive, leaving the promise of personalized care for this disease generally unfulfilled. Clinical decision making in colon cancer stands in stark contrast to the management of breast cancer, where the status of such markers as the estrogen receptor, progesterone receptor, HER2-neu, and a 21-gene recurrence score impact treatment planning. Similarly, the field has been outpaced by biomarker discoveries in non–small cell lung cancers, where crizotinib has been validated for treatment of ALK-rearranged tumors and EGFR inhibitors are validated for use in tumors that harbor EGFR mutations.3,4
Meanwhile, for a disease that is actually notable for its dearth of predictive biomarkers, commercially available molecular diagnostic assays are numerous and applied to colon cancer patients with surprising frequency. As clinicians, we are routinely engaged in complex discussions with patients regarding the role for or interpretation of these tests. Here, we review the biomarker discoveries in colon cancer and discuss the appropriate integration of relevant molecular diagnostic assays into clinical practice.
KRAS mutations in codons 12 and 13 of exon 2 are present in approximately 40% of colon cancers.5,6 When first analyzed, an enlarging body of literature concluded that KRAS codon 12 and 13 mutations are predictive of lack of response to monoclonal antibodies directed against EGFR that inhibit its downstream signaling pathways (cetuximab and panitumumab).1,5,7-13 Current National Comprehensive Cancer Network Guidelines recommend universal testing for KRAS mutations in codons 12 and 13 of exon 2 in patients with metastatic colon cancer,14 and FDA labels for both cetuximab and panitumumab recommend against their use in patients whose tumors harbor KRAS mutations.
More recent reports, however, have challenged this undiscriminating approach with data suggesting that KRAS codon 12 and 13 mutations may be distinct, despite coding for adjacent amino acids.15,16 In patients treated with cetuximab, the change of a glycine (G) to aspartic acid (D) at codon 13 of KRAS (c.38G>A, or p.G13D) was associated with survival that was intermediate between that of patients with KRAS wild-type tumors and tumors with a KRAS mutation at glycine-12.
The finding that G13D mutations may be associated with intermediate outcomes confounds our understanding of how KRAS mutations impact colon cancer prognosis.15,16 This should be considered hypothesis generating only; the clinical question of whether a patient with metastatic colon cancer harboring a KRAS G13D mutation will benefit from, be harmed, or be unaffected by anti-EGFR therapy remains unanswered. Accounting for the modest benefit of anti-EGFR therapy even among patients with KRAS wild-type tumors, the sample size necessary to prospectively answer this question is prohibitive. Currently, anti-EGFR agents are not recommended in routine practice for treatment of patients whose tumors have a G13D mutation and should only be used in the context of an investigational trial.14
The response rate to anti-EGFR monotherapy is approximately 15% among patients with KRAS codon 12 and 13 wild-type metastatic colorectal cancer.5 A number of retrospective and basic research studies have aimed to identify additional markers that may enrich for response. Rare KRAS mutations at codons 61 and 146 and activating mutations in other genes downstream of EGFR (eg, NRAS, BRAF, and PIK3CA) may predict decreased likelihood of benefit from cetuximab or panitumumab.17-20 At this time, however, there is insufficient evidence to restrict anti-EGFR therapy to patients with so-called “quadruple-negative” tumors (wild-type for KRAS, NRAS, BRAF, and PIK3CA).18,19 Similarly, the association between HER2 amplification or loss of PTEN expression with resistance to EGFR-targeted agents remains investigational.18,20
BRAF mutations are present in approximately 10% of colon cancers and are almost exclusively found in patients with wild-type KRAS. BRAF is a serine/threonine kinase immediately downstream of KRAS in the mitogen-activated protein kinase (MAPK) signaling pathway. BRAF-mutant colon cancers typically harbor a valine (V) to glutamic acid (E) change at codon 600 (c.1799T>A or p.V600E). BRAF mutations strongly associate with hypermutated tumors, frequently exhibiting a CpG island methylator phenotype and sporadic microsatellite instability (MSI).21-23 Similar to larger population-based studies, The Cancer Genome Atlas Network observed BRAF mutations in 3% of nonhypermutated and 47% of hypermutated colon cancers (n=165 and n=30, respectively).24
BRAF V600E is an adverse prognostic marker in metastatic colon cancer, independent of therapy.6,25-27 The presence of a BRAF mutation may diminish the more favorable prognosis afforded by MSI; the intersection of BRAF and MSI status is an area of ongoing investigation.6,27,28 Whereas KRAS codon 12 mutations clearly predict lack of benefit from EGFR-targeted antibodies, the predictive import of BRAF V600E is less certain. In a pooled analysis of the CRYSTAL and OPUS randomized clinical trials, the addition of cetuximab to first-line chemotherapy showed a nonsignificant trend toward improved progression-free survival (PFS) and overall survival (OS) for BRAF-mutant metastatic colon cancers.5 The CAIRO2 and COIN trials found that the poor prognosis associated with BRAF mutation was unchanged by cetuximab-containing first-line regimens.26,29 In the chemotherapy-refractory setting, patients with aggressive BRAF-mutant colon cancers are uncommon but appear unlikely to benefit from cetuximab.15,30
Personalized treatment is needed for patients with BRAF-mutated metastatic colon cancer. Vemurafenib transformed treatment of BRAF-mutated metastatic melanoma, but unfortuntately, single-agent efficacy of the BRAF inhibitor was minimal in colon cancer.31 Outcomes of combined inhibition of BRAF and MEK are more promising.32,33 As reported at the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting, among 34 patients with BRAF V600 mutant metastatic colon cancer treated with dabrafenib plus trametinib, 1 patient (3%) achieved a complete response and 3 patients (9%) achieved a partial response; 7 of 18 patients with disease stabilization achieved a minor response.32 Compared with melanoma, colon cancers have high EGFR expression and ligand production. Several preclinical studies suggest that signaling through EGFR is a key mechanism of resistance to BRAF inhibitors in colon cancer.34,35 Two multicenter phase 1/2 clinical trials combining a BRAF inhibitor with an EGFR-targeted antibody (NCT01750918 and NCT01719380) are now recruiting. We recommend consideration of screening all patients with KRAS wild-type metastatic colon cancer for a BRAF mutation based on its well-established negative prognostic value in this clinical context. Those positive for a mutation should be evaluated for clinical trial candidacy in light of their significantly poorer outcomes with standard therapy.
Multigene Recurrence Scores
There are currently several commercially available multigene assays that aim to inform decisions regarding the role for adjuvant chemotherapy in patients with stage II and III colon cancer. The first of these to be commercialized was the Oncotype DX Colon Cancer Assay (Genomic Health, Inc), which became available in January 2010.36 This assay quantifies expression of 7 recurrence-risk genes and 5 reference genes expressed in fixed, paraffin-embedded tumor specimens using reverse transcriptase-polymerase chain reaction to generate a score that corresponds to a low, intermediate, or high risk of recurrence.37 The clinical applicability of the recurrence score is strengthened by the identity of the genes and the fact that 6 of 7 genes reside in key pathways for cell cycle control (MKI67, MYC, MYBL2) and stromal response (FAP, BGN, INHBA).37 The seventh gene (GADD45B) is a marker of genotoxic stress and is thought to possibly regulate stromal response genes, including BGN.38
A retrospective validation of the Oncotype DX Colon Cancer Assay was performed using 1436 tissue blocks from patients in the randomized QUASAR study that compared adjuvant 5-fluorouracil with observation in patients with stage II disease; a continuum of low, intermediate, and high scores corresponded to estimated recurrence risk at 3 years of 12%, 18%, and 22%, respectively. According to these data, the Oncotype DX recurrence assay appears to discriminate the absolute increase in recurrence risk at 3 years by 10% along the continuum from low- to high-risk patients. Because the recurrence risk reduction from chemotherapy was proportional across all risk groups in the QUASAR data set, the assay has not been validated as a predictor of benefit from chemotherapy, although the benefit is marginally greater as the risk increases. A second validation study was performed on tumor specimens from 690 patients enrolled in CALGB 9581, which found no effect of adjuvant edrecolomab compared with observation in patients with resected stage II colon cancer.39 Multivariate analyses have demonstrated that recurrence scores were associated with risk of tumor recurrence and prognostic for outcome independent of conventional clinical and pathologic features.
ColoPrint (Agendia) and ColDx (Almac Group, Ltd) are 2 other commercially available assays that have been demonstrated in smaller validation sets to be prognostic for recurrence risk in stage II colon cancer patients. Similar to Oncotype DX, however, the prediction of recurrence risk for both is independent of other risk factors.40,41 While these assays provide information regarding the risk of recurrence, they also have failed to predict who benefits from chemotherapy.
While data may be insufficient to support the use of multigene assays in clinical decisions regarding the role for adjuvant therapy, we must consider that the features that are traditionally used to designate high risk of recurrence in stage II disease (eg, advanced tumor stage, tumor perforation, lymphovascular invasion, postsurgical analysis of fewer than 12 nodes, and poorly differentiated histology) are similarly prognostic but not predictive.42,43 Moreover, tumor grade and lymphovascular invasion are poorly reproduced and have not held up as prognostic factors in some studies. In fact, the Oncotype DX recurrence score provides independent value beyond tumor stage, lymphovascular invasion, number of nodes examined, and tumor grade.39 In our view, it is reasonable to consider the use of these recurrence scores, on a case-by-case basis, for patients with normal-risk stage II colon cancer cases without specific high- or low-risk features.
Applications of Molecular Profiling
As our knowledge of genomic data related to cancer has accumulated, the trend has led to the effort to enumerate a comprehensive description of the genomic alterations that define an individual’s tumor. Foundation Medicine and Caris Life Sciences provide 2 of many commercially available next-generation sequencing (NGS) assays marketed as FoundationOne and Molecular Intelligence, respectively. The FoundationOne assay performs deep sequencing of 236 known oncogenic genes, 48 introns, and 19 unique rearrangements, with a list of genes that continues to expand (or contract) with scientific discovery. This set of genes encompasses the usual suspects for all solid tumors and is not tailored to colon cancer. The Molecular Intelligence assay utilizes a variety of techniques, including immunohistochemistry, in situ hybridization, polymerase chain reaction, and NGS, to interrogate either a tumor-specific biomarker panel or a comprehensive gene panel, depending on preference. Both can be performed on formalin-fixed paraffin-embedded clinical samples.
In clinical application, these tests may be used to identify therapeutic options that are available through either clinical trial participation or off-label use of a drug approved for another indication. From a cohort of 40 colon cancer specimens analyzed with the FoundationOne assay, 21 (52.5%) were found to have at least one “actionable” alteration associated with potential sensitivity to targeted therapies, including KRAS, BRAF, FBXW7, PIK3CA, BRCA2, GNAS, CDK8, and a novel ALK gene fusion.44
Of course, identification of a potential target does not necessarily mean that a patient benefits from the therapeutic agent that is intended to hit that target. A prospective multicenter study was conducted using the Molecular Intelligence assay to match patients to treatments.45 While 84 of 86 (98%) patients who underwent molecular profiling of their refractory tumors had a molecular target identified, only 66 of 84 (78%) went on to receive a treatment according to molecular profiling results. Of these 66 patients, 18 (27%) had a PFS longer than on the regimen on which the patient had previously experienced disease progression. Four of the 11 patients with colon cancer had improvements of PFS ratios ?1.3. The lack of randomized design, wherein patients were essentially used as their own controls, limits the interpretation of these data. In addition, the ascertainment of its primary end point, PFS ratios, was potentially biased by imprecision in measuring the comparator progression-free interval used to determine PFS ratios as well as lack of blinding.
Whether the currently available molecular profiling technologies are sufficiently developed for meaningful clinical impact remains to be prospectively validated. Even so, several academic cancer centers have already launched or are actively engaged in the development of their own institutional molecular profiling panels. At the 2011 ASCO Annual Meeting, investigators from the MD Anderson Cancer Center reported an institutional analysis of up to 11 cancer-associated mutations in tissue for 1144 patients undergoing evaluation for participation in phase 1 clinical trials.46 In 60% of tumors, no mutations were identified. A single mutation was identified in one-third of the tumors. A matched investigational therapeutic option was available for 175 patients (15.3%). In comparison with patients who were treated with unmatched therapies, those patients who received treatment with a matched therapy sustained significantly better response rates (27% vs 5%; P<.0001) and improved median OS (13.4 vs 9.0 months; P=.017). This study is limited by the lack of randomization and its inability to fully distinguish the predictive strength of matched mutational analysis.
Heeding Heterogeneity – What to Biopsy?
Heterogeneity across and within tumors remains a considerable barrier to biomarker development. Genomic analyses from a single tumor biopsy potentially underestimate the mutational burden of intratumoral heterogeneity, thereby introducing bias into predictive biomarker studies. As an example, Gerlinger and colleagues reported a study of exome sequencing, chromosome aberration analysis, and ploidy profiling in multiple samples obtained from 4 primary renal carcinomas and their metastatic sites wherein intratumoral heterogeneity was observed for multiple tumor suppressor genes, and gene expression signatures varied widely in different regions of the same tumor.47 Variations between the primary tumor and metastatic sites (intertumoral heterogeneity) may also occur with varying frequency, depending on the biomarker of interest. Variation through acquisition or loss of biomarker expression or clonal drift over time (temporal heterogeneity) is also well described.48-50
Speaking to the heterogeneity of colon cancer as a disease and to the inadequacies of our current classification system, researchers presented a new taxonomy of 3 major intrinsic subtypes (A-, B-, and C-type) at the 2013 Gastrointestinal Cancers Symposium. From an unbiased gene expression analysis of 188 colon cancer patients of all stages, this molecular subtype classification was developed and subsequently validated in 543 patients with stage II and III disease. Three subtypes of colon cancer were characterized by unique biologic hallmarks, including epithelial-to-mesenchymal transition, deficiency in MMR genes, and cellular proliferation.51 Patients with A-type or B-type tumors exhibited a more proliferative and epithelial phenotype, better clinical outcomes, and were more likely to benefit from adjuvant chemotherapy. Patients with C-type tumors demonstrated mesenchymal gene expression phenotypes and did not benefit from adjuvant chemotherapy. Moreover, A-type and C-type tumors harbored a higher mutation frequency (4.2% and 6.2%, respectively) versus B-type tumors, which were associated with a low kinome mutation frequency (1.6%) concordant with their mismatch repair deficiency. BRAF mutations were seen in 39% of A-type tumors, 2% of B-type tumors, and 16% of C-type tumors. The development of this single sample predictor portends the eventual classification of colon cancer tumors according to intrinsic molecular subtypes that are associated with distinct biology and outcomes and consequently require unique treatment strategies.
As we enter into an era of clinical practice accompanied by expanding awareness and availability of NGS and other molecular profiling technologies, we face associated challenges of how to assimilate these technological advances into clinical practice. The market for predictive biomarkers in colon cancer has outpaced our ability to provide sound technical and clinical validation. Similarly, biomarker discovery has not been matched with companion drug discovery.52 As a result, premature implementation of these assays in the clinical setting has led to a healthy degree of skepticism as promises of clinical benefits have failed to mature with time.
The application of molecular profiling in our motivated and fit patients with life-threatening cancers who have failed standard therapies is enticing and may serve to reduce the time, expense, and opportunity cost of pursuing clinical trial eligibility without knowledge of biomarker test results. It also may facilitate a small portion of patients to access compassionate use programs for drugs that are in the later stages of development but not yet approved by the FDA for commercial use.
There remains a real risk, however, that the utilization of unvalidated assays outside of the research setting may disadvantage forward progress in this field and be counterproductive to the overarching goals of personalized medicine. Whenever a clinical decision is made to give or withhold a standard chemotherapy agent or to recommend participation in a clinical trial of an investigational targeted therapy, there is a non-negligible risk of harm to the patient. As an example, early detection of a BRAF mutation in a patient with a new diagnosis of colon cancer may result in a decision to forego standard chemotherapy regimens in favor of participation in a clinical trial of a BRAF-inhibiting therapy; however, this certainly poses a risk of both significant toxicity and lost opportunity to receive conventional therapies if the investigational option proves ineffective.
We advocate that the utility of predictive biomarkers must be linked to the treatment strategies whose benefit or risk they predict for. In the climate of increasing molecular testing capabilities, clinicians are urged to approach the commercially available biomarker tests with a healthy level of scrutiny toward clinical validation. We must continue to track and monitor outcomes and individual lessons learned from patients who undergo molecular profiling. At the current juncture, various commercially available assays may be of little added value unless they are studied cohesively with robust investigational therapeutic programs. While early data from clinical applications of molecular assays do suggest that a pairing of mutational analyses with investigational therapeutics may be a practice paradigm for the near future, these data also highlight the need for a seamless interface between predictive biomarkers and their companion drugs.
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38. Ungefroren H, Groth S, Ruhnke M, et al. Transforming growth factor-beta (TGF-beta) type I receptor/ALK5-dependent activation of the GADD45beta gene mediates the induction of biglycan expression by TGF-beta. J Biol Chem. 2005;280:2644-2652.
39. Venook AP, Niedzwiecki D, Lopatin M, et al. Biologic determinants of tumor recurrence in stage II colon cancer: validation study of the 12-gene recurrence score in cancer and leukemia group B (CALGB) 9581. J Clin Oncol. 2013;31:1775-1781.
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50. Montagut C, Dalmases A, Bellosillo B, et al. Identification of a mutation in the extracellular domain of the epidermal growth factor receptor conferring cetuximab resistance in colorectal cancer. Nat Med. 2012;18:221-223.
51. Simon 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). J Clin Oncol. 2012;30(suppl). Abstract 333.
52. Kelley RK, Atreya C, Venook AP, et al. Predictive biomarkers in advance of a companion drug: ahead of their time? J Natl Compr Canc Netw. 2012;10:303-309.
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