Genomic Testing in Colorectal Cancer: How Much Is Enough? Published on Cancer Network (http://www.cancernetwork.com)

Genomic Testing in Colorectal Cancer: How Much Is Enough? March 15, 2015 | Oncology Journal [1], Cancer and Genetics [2], Colorectal Cancer [3],Gastrointestinal Cancer [4]By Rodrigo Dienstmann, MD [5], Ramon Salazar, MD, PhD [6], and Josep Tabernero, MD, PhD [7]

The identification and characterization of gene signatures, driver events, and pharmacogenomics inmolecularly homogeneous subsets of patients is likely to advance effective drug developmentstrategies in colorectal cancer.

Colorectal cancer has been extensively molecularly characterized in recent years. In addition tofurthering the understanding of biologic hallmarks of the disease, the ultimate goal of these studieshas been to provide tools that would allow us to identify subgroups of colorectal cancer withprognostic and predictive implications, either for the anticipation of toxicity or for selection of thebest therapy, or both. As a result of these efforts, multiple genomic tests have become available forclinical use in early-stage and advanced colorectal cancer. Goldstein and colleagues have carefullyreviewed the cost-effectiveness of these tests in this issue of ONCOLOGY[1]; their evaluation istimely, considering the widespread availability of high-throughput technologies for genomic profiling.

The authors recognize that the cost-effectiveness of a prognostic test can be easily measured only ifit specifically guides treatment decisions. Given the lack of validated predictive biomarkers forbenefit from adjuvant chemotherapy in early-stage colorectal cancer, clinicians are left with onlyprognostic tests that estimate risk of relapse to help them with treatment individualization. Becauseof the modest therapeutic benefit of fluorouracil (5-FU)-based treatment, prognostic biomarkers forits use have their greatest potential benefit in stage II disease, a setting in which they can facilitatethe identification of subsets of patients with lower or higher risk of relapse and for whom adjuvantchemotherapy could be avoided or favored, respectively. Microsatellite instability (MSI), for example,has been consistently associated with low recurrence rates and a very good outcome withoutadjuvant treatment, supporting a no-adjuvant-treatment approach in patients with MSI tumors.On the other hand, predictions of poor prognosis based on pathologic factors have not beenconsistently tied to benefit from adjuvant chemotherapy in stage II colorectal cancer,[2] raisingconcern about the real value of complex alternative tests such as prognostic gene expressionsignatures in this setting. These genomic signatures could have the greatest clinical utility ascomplements to analysis of T stage and MSI status, specifically for patients who have pT3microsatellite stable (MSS) stage II disease. The Oncotype DX colon cancer gene expression array isthe prognostic score that has been most widely validated, and despite a high score being anindependent risk factor for recurrence in multivariable models, differences in outcomes for low-riskand high-risk patients are only modest from a clinical perspective. Cross-comparison of Oncotype DXscores with poor-risk clinical and pathologic factors, such as those recommended by the NationalComprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), andEuropean Society for Medical Oncology (ESMO) guidelines, has not been extensively conducted.Prospective empiric evidence is scarce, and the test does not influence the treatment decision in themajority of patients.[3] Furthermore, economic studies assessing the cost-effectiveness of thesesignatures for selecting patients with colorectal cancer at high risk for recurrence (and for basingadjuvant chemotherapy decision making on this criterion) are not yet available.Focusing on advanced colorectal cancer, in which validated and clinically useful predictive markersare widely used to select anti–epidermal growth factor receptor (EGFR) therapy, the absence ofspecific sensitivity/resistance patterns for infrequent mutant alleles in KRAS, NRAS, or BRAF genesshould not prevent clinicians from ordering extended RAS testing to help tailor therapy. There are anumber of justifications for this approach. First, in some prospective randomized trials, a detrimentaleffect has been observed with the addition of anti-EGFR agents to chemotherapy in patients whosetumors harbor mutations in KRAS beyond codons 12 and 13 or in NRAS.[4-6] Second, followingadvances in next-generation sequencing, the development of targeted agents for use in treatingcolorectal cancer is moving from the “one test–one drug” paradigm to a genomically stratifiedmodel.[7] Early clinical trials have shown that targeted therapies matched against KRAS, NRAS, or

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Genomic Testing in Colorectal Cancer: How Much Is Enough? Published on Cancer Network (http://www.cancernetwork.com)

BRAF mutations may offer promising treatment opportunities in colorectal cancer. Specifically for theBRAF V600 population, studies have shown that treatment with selective BRAF inhibitors incombination with other targeted agents (EGFR, mitogen-activated protein/extracellularsignal-regulated kinase [MEK], and/or phosphatidylinositol 4,5-bisphosphate 3-kinase [PI3K]inhibitors) can lead to unprecedented response rates in highly chemo-refractory patients.[8,9] Insummary, given the potentially detrimental effects of anti-EGFR therapies and the benefitdemonstrated in early clinical trials with novel agents, the cost-effectiveness of extended RAS-BRAFmutation profiling needs to be reexamined.The potential benefits of multiplexed genotyping platforms in individual patients with colorectalcancer have already been demonstrated, and the next logical step is to facilitate larger clinical trialswith biomarker-driven therapies. However, there are many obstacles for implementation ofnext-generation sequencing in clinical practice:■ Unsolved biologic questions.o How to integrate and make biologic sense of the substantial amounts of genomic data?• How to distinguish a driver from a passen- ger genetic aberration?• How to deal with incidental findings?• How to define which mutations engender sensitivity to specific targeted agents?• How to select therapy in the case of multiple aberrations?o Should profiling be of primary tumor or of real-time biopsies of metastatic sites? Clonal evolution,selection pressure from prior therapies, and tumor heterogeneity may affect the results.■ Scientific concerns regarding platform selection and turnaround time: need for standardization inthe collection, handling, and storage of specimens, and in bioinformatics pipelines.■ Logistical issues related to prescreening strategies: in whom, when, and where (local pathologylab or centralized lab?) to perform molecular profiling.■ Challenges in ethical and economic domains: setting up certified labs, costs of diagnostic testsand biopsies, off-label use of targeted therapies.Moreover, to implement true personalized medicine, we should also consider the characteristics ofthe host-tumor relationship (tumor microenvironment and immune response) and host-drugrelationship (metabolism genes and pharmacogenomics). As described by the authors, althoughmany strategies have been developed for assessing dihydropyrimidine dehydrogenase (DPD) activityto guide 5-FU dosing, none has been properly validated for clinical utility. An alternativepharmacokinetically guided approach has indeed been proven to be cost-effective but is logisticallymore complex.[10] Uridine 5'-diphospho-glucuronosyltransferase 1A1 (UGT1A1) testing to guideirinotecan dosing is more promising, although the very low prevalence of the genetic variation linkedto substantial hematologic toxicity at the standard doses used in the clinics largely compromises itsutility. However, cost-effectiveness may change favorably when the test is used to identify a largersubpopulation that can tolerate higher doses of irinotecan, with increased response rates as seen inmultiple phase I trials.[11-13]. Larger phase II trials of genotype-directed tailored irinotecan dosing inadvanced colorectal cancer are ongoing.To conclude, we believe that the identification and characterization of gene signatures, driverevents, and pharmacogenomics in molecularly homogeneous subsets of patients is likely to advanceeffective drug development strategies in colorectal cancer. Many challenges must be overcomebefore genomic-driven trials and personalized cancer medicine can become a reality and supplantcurrently accepted modalities. As costs decrease for next-generation sequencing and otherhigh-throughput technologies, the clinical and economic impact of genomic tests in colorectal cancerwill need to be revisited.Financial Disclosure: The authors have no significant financial interest or other relationship withthe manufacturers of any products or providers of any service mentioned in this article. References: 1. Goldstein DA, Shaib WL, Flowers CXR. Cost and effectiveness of genomic testing in themanagement of colorectal cancer. Oncology (Williston Park). 2015;29:175-83.

2. O’Connor ES, Greenblatt DY, LoConte NK, et al. Adjuvant chemotherapy for stage II colon cancerwith poor prognostic features. J Clin Oncol. 2011;29:3381-8.

3. Srivastava G, Renfro LA, Behrens RJ, et al. Prospective multicenter study of the impact ofoncotype DX colon cancer assay results on treatment recommendations in stage II colon cancer

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Genomic Testing in Colorectal Cancer: How Much Is Enough? Published on Cancer Network (http://www.cancernetwork.com)

patients. Oncologist. 2014;19:492-7.

4. Douillard JY, Oliner KS, Siena S, et al. Panitumumab-FOLFOX4 treatment and RAS mutations incolorectal cancer. New Engl J Med. 2013;369(11):1023-34.

5. Heinemann V, von Weikersthal LF, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plusbevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): arandomised, open-label, phase 3 trial. Lancet Oncol. 2014;15:1065-75.

6. Seymour MT, Brown SR, Middleton G, et al. Panitumumab and irinotecan versus irinotecan alonefor patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): aprospectively stratified randomised trial. Lancet Oncol. 2013;14:749-59.

7. Dienstmann R, Rodon J, Barretina J, Tabernero J. Genomic medicine frontier in human solidtumors: prospects and challenges. J Clin Oncol. 2013;31:1874-84.

8. Tabernero J, van Geel R, Bendell JC, et al. Phase I study of the selective BRAFV600 inhibitorencorafenib (LGX818) combined with cetuximab and with or without the a-specific PI3K inhibitoralpelisib (BYL719) in patients with advanced BRAF mutant colorectal cancer. Eur J Cancer.2014;50(suppl 6): abstr 11LBA.

9. Bendell JC, Atreya CE, Andre T, et al. Efficacy and tolerability in an open-label phase I/II study ofMEK inhibitor trametinib (T), BRAF inhibitor dabrafenib (D), and anti-EGFR antibody panitumumab (P)in combination in patients (pts) with BRAF V600E mutated colorectal cancer (CRC). J Clin Oncol.2014;32(5s; abstract 3515).

10. Goldstein DA, Chen Q, Ayer T, et al. Cost effectiveness analysis of pharmacokinetically-guided5-fluorouracil in FOLFOX chemotherapy for metastatic colorectal Cancer. Clin Colorectal Cancer.2014;13:219-25.

11. Toffoli G, Cecchin E, Gasparini G, et al. Genotype-driven phase I study of irinotecan administeredin combination with fluorouracil/leucovorin in patients with metastatic colorectal cancer. J Clin Oncol.2010;28:866-71.

12. Marcuello E, Páez D, Paré L, et al. A genotype-directed phase I-IV dose-finding study of irinotecanin combination with fluorouracil/leucovorin as first-line treatment in advanced colorectal cancer. Br JCancer. 2011;105:53-7.

13. Kim KP, Kim HS, Sym SJ, et al. A UGT1A1*28 and *6 genotype-directed phase I dose-escalationtrial of irinotecan with fixed-dose capecitabine in Korean patients with metastatic colorectal cancer.Cancer Chemother Pharmacol. 2013;71:1609-17. Source URL: http://www.cancernetwork.com/oncology-journal/genomic-testing-colorectal-cancer-how-much-enough

Links:[1] http://www.cancernetwork.com/oncology-journal[2] http://www.cancernetwork.com/cancer-and-genetics[3] http://www.cancernetwork.com/colorectal-cancer[4] http://www.cancernetwork.com/gastrointestinal-cancer[5] http://www.cancernetwork.com/authors/rodrigo-dienstmann-md[6] http://www.cancernetwork.com/authors/ramon-salazar-md-phd[7] http://www.cancernetwork.com/authors/josep-tabernero-md-phd

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