Anticipating the clinical use of prognostic gene expression-based tests for colon ... · 2013. 10....
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Anticipating the clinical use of prognostic gene expression-based
tests for colon cancer stage II and III: Is Godot finally arriving?
Anita Sveen1,2, Arild Nesbakken2,3, Trude H. Ågesen1,2, Marianne G. Guren4, Kjell M. Tveit4,
Rolf I. Skotheim1,2, Ragnhild A. Lothe1,2
1Department of Cancer Prevention, Institute for Cancer Research, The Norwegian Radium
Hospital, Oslo University Hospital, Oslo, Norway
2Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway
3Department of Gastrointestinal Surgery, Oslo University Hospital, Oslo, Norway
4Department of Oncology, Oslo University Hospital, Oslo, Norway
Running title: Prognostic gene expression signatures of colon cancer
Keywords: clinical test; colon cancer; gene expression; prognosis; stage II and III
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Financial support: This study is supported by the South-Eastern Norway Health Authority
(Research Grant “Genome Medicine of Colorectal Cancer”, project number 2011024, to RAL,
supports AS as post doc)
Corresponding author: Ragnhild A. Lothe, Department of Cancer Prevention, Institute for
Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, P.O.Box 4953
Nydalen, NO-0424 Oslo, Norway; Phone: +47 - 2278 1728; Fax: +47 - 2278 1745; E-mail:
Authors’ disclosures of potential conflicts of interest: Patent applications have been filed for
ColoGuideEx and ColoGuidePro by the hospital technology transfer office, Inven2. The authors
have no further disclosures.
Word count: 1,735
Total number of figures and tables: 2
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Translational relevance
Identification of patients with colon cancer stage II and III who will benefit from adjuvant
treatment is a major clinical challenge. A significant proportion of patients treated with surgery
alone experiences relapse, while some patients receiving chemotherapy would be cured with
surgery alone. The use of gene expression-based tests, in conjunction with clinicopathological
parameters, has clear potential for improved treatment decisions based on risk assessment.
Several prognostic gene expression-based tests have been proposed for this purpose. However,
clinical implementation is awaiting prospective validation. For colon cancer stage II, clinical
trials are underway and this prospect has never been closer. For colon cancer stage III, clinical
relevance is limited to patients that are not routinely offered adjuvant chemotherapy, in particular
elderly patients. Promising results are emerging also for this patient subgroup.
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Abstract
Purpose: According to current recommendations for adjuvant treatment, patients with colon
cancer stage II are not routinely offered chemotherapy, unless considered to have a high risk of
relapse based on specific clinicopathological parameters. Following these criteria, it is
challenging to identify the subgroup of patients that will benefit the most from adjuvant
treatment. Contrarily, patients with colon cancer stage III are routinely offered chemotherapy, but
due to expected adverse effects and frailty, elderly patients are often excluded from standard
protocols. Colon cancer is a disease of the elderly and accordingly, there is a large subgroup of
patients for which guidelines for adjuvant treatment remain less clear. In these two clinical
settings, improved risk stratification has great potential impact on patient care, anticipating that
high risk patients will benefit from chemotherapy. However, microsatellite instability is the only
molecular prognostic marker recommended for clinical use.
Experimental Design: In this perspective, we provide an updated view on the status and clinical
potential of the many proposed prognostic gene expression-based tests for colon cancer stage II
and III.
Results: The main limitation for clinical implementation is lack of prospective validation. For
patients with stage II, highly promising tests have been identified and clinical trials are ongoing.
For elderly patients with stage III, the value of such tests has received less focus, but promising
early results have been shown.
Conclusion: Although awaiting results from prospective trials, improved risk assessment for
patients with stage II and III is likely to be achieved in the foreseeable future.
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Introduction
The question of whether to treat patients with colon cancer stage II with adjuvant chemotherapy
remains among the most challenging questions in oncology (1). Although approximately 20% of
patients with stage II relapse after surgery, improvements in survival upon treatment with
chemotherapy is very low for this patient group as a whole, and adjuvant therapy is not
recommended as standard of care (2-6). Rather, the choice of adjuvant therapy for the individual
patient with colon cancer stage II is based on clinicopathological high-risk factors, including
stage pT4 (invasion of serosal surface or adjacent organs), poor differentiation, lymphatic or
vascular invasion, bowel obstruction or perforation, emergency surgery, incomplete tumor
resection and inadequate number of lymph nodes sampled (<12; 7). In a recent study by
O’Connor et al., reporting on a representative population of almost 25,000 patients with stage II
(aged 65 years or older), as many as 75% of the patients were categorized with at least one poor
prognostic feature (8). No survival benefit from adjuvant treatment was found for this high-risk
patient group. Furthermore, there was only a 2% difference in the frequency of use of adjuvant
therapy between the high- and low-risk groups (8). Accordingly, improvements to risk
stratification continue to have great potential benefit for patient care in colon cancer stage II.
In contrast, adjuvant treatment of patients with colon cancer stage III is considered one of the
greater success stories of gastrointestinal oncology (9). This is due to a more than 10% absolute
improvement in survival for patients receiving fluorouracil-based treatment, and another 4% by
addition of oxaliplatin (3, 10-13). However, although standard protocols recommend adjuvant
chemotherapy for all medically fit patients with stage III disease (6, 7), only a little more than
half of the patients reported by O’Connor et al. (57% of 18,185 patients with stage III) actually
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did receive such treatment (8). This is consistent with previous reports of underuse of adjuvant
chemotherapy (14). In particular, the use of chemotherapy decreases with increasing patient age
and comorbidity (8, 15). Elderly patients are often underrepresented in clinical trials, hence there
is little data on the trade-off between efficacy and toxicity (16). However, it was recently reported
that patients older than 75 years have a similar magnitude of survival benefit from fluorouracil-
based treatment as younger patients (17, 18). The high age of patients with colon cancer (40% are
older than 75 years at the time of diagnosis) and the increasing life expectancy in general,
therefore emphasize the importance of guidance of treatment options by improved risk
stratification also for this patient group (16).
Overview of gene expression-based prognostic tests
In contrast to anticipations, to the pioneering success in breast cancer (reviewed in 19), and
despite the large number of proposed gene expression-based assays (overview in Table 1),
clinical guidelines for colon cancer explicitly express that no multi-gene assays are currently
recommended for use in risk assessment and determination of adjuvant treatment (6, 7).This is a
natural consequence of the lack of large prospective trials designed to evaluate their clinical
value. Such trials are still considered the gold standard for evaluation of biomarkers, albeit with
suggested alternatives to the conventional setting with randomized, controlled trials (20-22). As
evident from Table 1 and several previous reviews (23-27), the main limitations of the proposed
assays are small sample sizes and unsatisfactory or lacking validation in independent patient
series.
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However, changes are on the horizon. To our knowledge, five tests have now been launched,
including Oncotype Dx® Colon Cancer (Genomic Health, Inc., Redwood City, CA, U.S.);
ColonPRS® (Signal Genetics LLC, New York, NY, U.S.); ColoPrint® (Agendia NV,
Amsterdam, the Netherlands); GeneFx® Colon (Precision Therapeutics, Inc., Pittsburg, PA,
U.S.); and OncoDefender™-CRC (Everist Genomics, Inc., Ann Arbor, MI, U.S.). All these tests
have been shown to have prognostic value in independent patient series, although the designs and
sample numbers of the validation analyses have varied (Table 1; see also previous reviews of
ColoPrint®, Oncotype Dx® Colon Cancer and GeneFx® Colon; 25, 28, 29). In addition, we have
recently published two new tests, ColoGuideEx (30) and ColoGuidePro (31), performing
development and successful validation in three independent patient series across populations and
microarray platforms (Table 1).
Currently, Oncotype Dx® Colon Cancer is the only test that is available outside of research
settings, although it has not yet been recommended for clinical use (32). This is the test for which
prognostic potential has been most thoroughly validated (Table 1; 33, 34, 35). Furthermore, for
evaluation of ColoPrint®, patients are being recruited to the PARSC prospective trial
(NCT00903565) to assess performance in estimating 3-year relapse rates for colon cancer stage II
(36). This is the first trial that has been specifically designed to assess the prognostic value of a
gene expression signature in colon cancer. The trial has been designed as an observational rather
than a randomized, controlled study. Although this is regarded to yield lower levels of evidence
of clinical value, it exemplifies an agreement between feasibility and clinical relevance that can
provide an adequate foundation for recommendations of clinical implementation (37).
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Clinical potential
Gene expression signatures are likely to be implemented in the clinic as supplemental rather than
individual prognostic tests (19). In stage II and III colon cancer, important factors to consider in
this respect are the conventional clinicopathological prognostic markers, primarily the previously
mentioned high-risk factors for stage II disease. Also, molecular subtypes should be taken into
consideration. Following validation of prognostic potential in several studies (38-40),
microsatellite instability (MSI)-status of the tumor is now suggested for clinical use in stage II (7,
41). Patients whose tumors have a high level of MSI have a favorable prognosis and improved
outcome seems to be confined to patients with stage II disease (42). Gene expression-based tests
for stage II colon cancer should provide prognostic information independent of these factors.
Most of the proposed prognostic gene expression signatures for colon cancer have focused on
stage II, due to the unambiguous clinical potential for improved selection of patients with a high
risk of relapse and higher expected benefit from adjuvant chemotherapy (Figure 1). GeneFx®
Colon, OncoDefender™-CRC and ColoGuideEx have been developed specifically to identify
patients with stage II and a high risk of relapse (30, 43, 44). Oncotype Dx® Colon Cancer was
developed also for patients with stage III disease (34), but validation analyses have been
restricted to patients with stage II (retrospective analysis of 711 and 690 selected patients from
two clinical trials; 33, 35). Similarly, the primary objective of the PARSC trial is to assess the
value of ColoPrint® for patients with stage II (n = 575; 36), and the test has been launched for
this patient group only (45). Prognostic potential independent of many of the high-risk factors of
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stage II colon cancer has been shown retrospectively for these tests by multivariate validation
analyses. Also, independence of MSI-status has been validated for Oncotype DX® Colon Cancer
(33, 35) and ColoPrint® (46, 47). Importantly, among the secondary objectives of the PARSC
trial is comparison of risk assessment according to ColoPrint® and the ASCO high-risk criteria
(2).
The more ambiguous clinical potential of prognostic gene expression signatures for patients with
colon cancer stage III has limited the number of studies with this focus. Considering that almost
half the patients will be cured with surgery alone, it is clear that current adjuvant treatment
standards result in substantial over-treatment (3). Still, clinical implementation of gene
expression signatures to identify stage III patients that can safely be treated by surgery alone, has
been deemed unlikely (29). This will depend on confident identification of patients with low risk
of relapse. Accordingly, clinical relevance is limited to subgroups of patients for which standard
protocols do not apply, for example to elderly patients (Figure 1). Among the proposed gene
expression-based tests, independent prognostic value for patients with stage III colorectal cancer
has been successfully retrospectively validated for ColoPrint® (n = 62; 46) and ColoGuidePro (n
= 107; 31). Although based on small sample numbers and further validation is needed,
ColoGuidePro is the only test that has demonstrated prognostic potential in the clinically relevant
subgroup of patients with colon cancer stage III that are 75 years or older.
Additional issues to consider for the clinical utility of prognostic gene expression signatures are
technical issues regarding sampling procedures and methodologies for measuring gene
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expression. These technical issues have been a source of some variation among the proposed tests
(Table 1). Applicability to formalin-fixed, paraffin-embedded (FFPE) samples is in agreement
with current hospital routines for sample processing. Tests that are applicable to FFPE samples,
for example the Oncotype DX® Colon Cancer assay, also have the advantage of availability of
archived material for collection of large patient cohorts for retrospective analyses (33-35).
However, FFPE material commonly contains partially degraded RNA, producing less reliable
gene expression measures compared with fresh frozen tissue (26). Furthermore, the technology
used for gene expression analysis has alternated between microarray- and quantitative PCR-based
analysis (Table 1). The former has allowed for genome-wide analyses and the latter has been
limited to pre-selected sets of genes. The diagnostic use of both technologies has been
successfully established for prognostic assessment of breast cancer. Lastly, pricing is also an
important issue for clinical implementation. The cost of the Oncotype DX® Colon Cancer assay
is arguably high at $3,200. Still, cost-effectiveness analyses have indicated cost benefit for
patients with pT3 stage II colon cancer, when taking into account the concomitant reduction in
use of adjuvant chemotherapy (48).
In conclusion, several promising gene expression-based tests have been proposed for risk
assessment of stage II colon cancer. The clinical implementation of these tests is still detained by
insufficient validation, but this prospect has never been closer. Results from clinical trials are
anticipated to provide the answer to which tests may aid in the persistent clinical challenge of
identifying patients at high risk of relapse and accordingly, have expected larger benefit from
chemotherapy. For stage III colon cancer, the decision against adjuvant treatment of patients with
good prognosis is an ethically challenging implication of risk stratification. However, the use of
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gene expression-based signatures to determine risk of relapse in elderly and frail patients, who
are more vulnerable to chemotherapy, may present a valuable clinical advance. Also emerging as
a likely scenario from the ongoing genome sequencing efforts, is the combined forces of
prognostication and companion diagnostics, to identify patients with high-risk stage II and III
disease who may benefit also from targeted therapy.
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Table 1. Proposed gene expression signatures for prognostic assessment of colorectal cancer stage II and III
Study No. of
markers in signature
Cancer type
Tumor stage
No. of patient/tumor samples analyzed Sample type
Assay for clinical testing Test development Validation (independent samples)
Microarray-based tests:
Bertucci et al., Oncogene 2004;23:1377-91
235 CRC II & III 9 - FF -
Kwon et al., Dis Colon Rectum 2004;47:141-52
60 CRC II & III 12 - FF -
Wang et al., J Clin Oncol 2004;22:1564-71
23 CC II 38
(a) 36
FF - (b) 50 (separate study; Barrier et al., J Clin Oncol
2006;24:4685-90) (c) 123 (separate study; Jiang et al., J Mol Diagn
2008;10:346-54) Eschrich et al., J Clin Oncol 2005;23:3526-35
43 CRC II & III 45 95 FF -
Arango et al., Gastroenterology 2005;129:874-84
17 CRC III 25 - FF -
Barrier et al., Oncogene 2005;24:6155-64
30 CC II & III 18 - FF -
Barrier et al., Dis Colon Rectum 2005;48:2238-48
47 CC II & III 12a - FF -
D'Arrigo et al., Int J Cancer 2005;115:256-62
29 CRC II & IV 20 - FF -
Barrier et al., J Clin Oncol 2006;24:4685-90
30 CC II 50 - FF -
Bandres et al., Oncol Rep 2007;17:1089-94
8 CC II 16 27 (stage II & III; qPCR of 5 genesb) FF -
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Barrier et al., Oncogene 2007;26:2642-8
70 CC II 24a - FF -
Cavalieri et al., Oncol Res 2007;16:535-48
8 CRC III & IV 19 55 (stage I-IV; qPCR of 2 genesb) FF -
Yamasaki et al., Int J Oncol 2007;30:129-38
119 CRC I-IV 58 28 (stage II & III) FF -
Lin et al., Clin Cancer Res 2007;13:498-507
22 CRC I-IV
149 Reciprocal validation between gene signatures and patient cohorts
FF - 19 55
Jiang et al., J Mol Diagn 2008;10:346-54
7c CC II 123 110 (qPCR) FF & FFPE
-
Anjomshoaa et al., Br J Cancer 2008;99:966-73
36 CC I-IV 145 - FF -
Watanabe et al., Cancer 2009;115:283-92
45 CRC III 36 - FF -
Staub et al., J Mol Med 2009;87:633-44
112 CRC I-IV 62 - FF -
Jorissen et al., Clin Cancer Res 2009;15:7642-51
128 CRC II & III 188
(a) 79 (selected patients; restricted gene signature)
FF - (b) 37 (separate study, not satisfactory results; Thorsteinsson et al., Int J Colorectal Dis 2012;27:1579-
86) Smith et al., Gastroenterology 2010;138:958-68
34 CC I-IV 55 177 (successfully also for stage II & III independently) FF -
Matsuyama et al., Int J Cancer 2010;127:2292-9
27 CRC I-IV 77 73 (stage II & III; qPCR of 1 gene) FF -
Peng et al., Int J Colorectal Dis 2010;25:1277-85
8d CRC II & III 95 - FF -
Salazar et al., J Clin Oncol 2011;29:17-24
18 CRC I-IV 188 (a) 206 (stage I-III; successfully also for stage II & III
independently) FF ColoPrint® (b) 135 (stage II; separate study; Maak et al., Ann Surg
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2013; 257:1053-8) Kennedy et al., J Clin Oncol 2011;29:4620-6
634 CC II 215 144 FFPE GeneFx®
Colon
Ågesen et al., Gut 2012;61:1560-7
13e CRC II 44
(a) 52
FF ColoGuideEx (b) 108 (Data from Jorissen et al., Clin Cancer Res 2009;15:7642-51 and Smith et al., Gastroenterology
2010;138:958-68) Sveen et al., Clin Cancer Res 2012;18:6001-10
7e CRC II & III 172 215 (successfully also for stage III independently; Data from Jorissen et al., Clin Cancer Res 2009;15:7642-51 and Smith et al., Gastroenterology 2010;138:958-68)
FF ColoGuidePro
qPCR-based tests (pre-selected genes):
Schetter et al., Clin Cancer Res 2009;15:5878-87
9 CC I-IV 113 73 FF -
Pillaire et al., Oncogene 2010;29:876-87
7 CRC I-IV 75 - FF -
O'Connell et al., J Clin Oncol 2010;28:3937-44
12 CC II & III 1,851
(a) 711 (stage II; separate study; Gray et al., J Clin Oncol 2011;29:4611-9)
(b) 690 (stage II; separate study; Venook et al., J Clin Oncol 2013; 31:1775-81)
FFPE Oncotype DX® Colon Cancer
Carvalho et al., Oncol Rep 2011;25:1321-7
1 CRC III 52 - FF -
Giráldes et al., Int J Cancer 2012;10.1002/ijc.27747
2 CC II & III 228 - FFPE -
Lenehan et al., Cancer 2012;118:5234-44
5 CRC I & II 74 264 FFPE OncoDefender
™-CRC
Tests developed from publically available gene expression data:
van Laar et al., Br J Cancer 2010;103:1852-7
163 CC I-IV
232 (Data from Smith et al.,
Gastroenterology 2010;138:958-68)
60 (Data from stage II & III; Jorissen et al., Clin Cancer Res 2009;15:7642-51)
- ColonPRS®
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Merlos-Suarez et al., Cell Stem Cell 2011;8:511-24
71 CRC I-IV
345 (Data from Jorissen et al., Clin Cancer Res 2009 and 15:7642-51;
Smith et al., Gastroenterology 2010;138:958-68)
- - -
Oh et al., Gut 2012;61:1291-8
114 CRC I-IV
177 (Data from Smith et al.,
Gastroenterology 2010;138:958-68)
(a) 117 (subset of 80 probes; Data from Staub et al., J Mol Med 2009;87:633-44 and Smith et al.,
Gastroenterology 2010;138:958-68) - -
(b) 96 (stage I-III; unsuccessfully for the subset of 80 probes; Data from Jorissen et al., Clin Cancer
Res 2009;15:7642-51)
Shi et al., PLoS One 2012;7:e41292f
487 CRC II & III
111 (Data from Smith et al.,
Gastroenterology 2010;138:958-68)
67 (Data from Jorissen et al., Clin Cancer Res 2009;15:7642-51)
- -
aNon-neoplastic colonic mucosa adjacent to tumors bUnivariate prognostic associations cRefinement of previously reported signature
(Wang et al., J Clin Oncol 2004;22:1564-71) dcDNA mediated annealing, selection, extension and ligation (DASL) assay of 502 genes
eIdentified using exon resolution microarrays fMeta-analysis; CC, colon cancer; CRC, colorectal cancer; FF, fresh frozen; FFPE,
formalin-fixed, paraffin-embedded; qPCR, quantitative PCR. Note that the references in the left column appear in the reference list
only if they are also cited in the text.
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Figure legend
Figure 1. Clinical potential of prognostic gene expression-based tests for colon cancer stage
II and III. According to standard protocols, adjuvant treatment of patients with colon cancer
stage II and III is decided by assessment of risk of relapse after surgical resection. For patients
with stage II (left), this currently relies on clinicopathological high-risk parameters (listed in the
Introduction), and MSI-status is also recommended for consideration. Several gene expression-
based tests have shown great potential for improvement of risk assessment for patients with stage
II (blue). Colon cancer stage III presents with lymph node metastases (right) and these patients
are routinely offered adjuvant treatment. However, elderly and frail patients are less commonly
treated with chemotherapy. For patients older than 75 years, clinical guidelines are less clear and
improved prognostic assessment could aid in the decision to treat. This patient group has received
less focus and no prognostic gene expression-based tests have been thoroughly validated for
elderly patients alone. However, ColoGuidePro has been shown to have potential from analyses
of a small patient series. For patients with stage III in general, prognostic potential has been
shown also for ColoPrint®. MSI, microsatellite instability
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Published OnlineFirst October 28, 2013.Clin Cancer Res Anita Sveen, Arild Nesbakken, Trude H. Ågesen, et al. Godot finally arriving?expression-based tests for colon cancer stage II and III: Is Anticipating the clinical use of prognostic gene
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