KRAS mutational status assessment in patients with metastatic colorectal cancer: are the clinical implications so clear?
ABSTRACT The CRYSTAL study demonstrated an advantage in terms of objective response and progression-free survival for the FOLFIRI-cetuximab combination compared with first-line FOLFIRI for patients with metastatic colorectal cancer. The results of an ancillary biological study with screening for a KRAS gene mutation in 540 patients were reported at the 2008 American Society of Clinical Oncology congress. The analysis confirmed the value of adding cetuximab only in the absence of KRAS mutation. These results led to recommend restriction of the use of cetuximab in Europe to patients with a tumour bearing wild-type KRAS. How should this apparent simplification be integrated into clinical practice? The FOLFIRI-cetuximab combination is certainly a useful supplementary first-line option although its place in relation to other high-dose regimens (high-dose FOLFIRI, FOLFOXIRI or FOLFOX-7), conventional chemotherapy plus bevacizumab, or even a fluoropyrimidine alone in the case of unresectable metastases, has yet to be specified. For subsequent lines, no study has prospectively assessed the value of the chemotherapy--anti-epidermal growth factor receptor combination as a function of KRAS status. Should the absence of objective response constantly observed in retrospective analyses in patients with a tumour presenting a KRAS mutation definitively exclude these patients while stable disease (and potentially a slight gain in survival) may be obtained?
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ABSTRACT: The KRAS oncogene has been extensively studied for more than three decades, however, it is only recently that it attained a central role in the clinical decision-making process for the practicing oncologist. Recently, based on retrospective analyses of large randomized clinical trials, the use of anti-epidermal growth factor (EGFR) monoclonal antibodies, cetuximab and panitumumab, was restricted to patients with metastatic colorectal cancer that carry the "wild-type"KRAS genotype. Challenges remain in the laboratory implementation of KRAS mutational testing and the clinical application of the test for treatment planning. This review attempts to offer a global view of KRAS biology, its functional role in cell signaling, mechanisms of resistance to anti-EGFR agents and its predictive potential in metastatic colorectal cancer. We also survey the growing list of candidate biomarkers that may shortly supplement KRAS in routine clinical patient stratification. Finally, we discuss practical aspects of KRAS testing that may be useful for those involved in mutational screening in their centers. This general overview of KRAS for clinical oncology practice aims to assist in data interpretation and offer insight into potential pitfalls of mutational testing. KRAS is a prime example of how translational research can fulfill the promises of personalized medicine for tailoring treatment to match the underlying tumor biology.Cancer Treatment Reviews 05/2011; 37(3):221-33. · 6.02 Impact Factor
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ABSTRACT: Zebra finches are a highly social and monogamous avian species. In the present study, we sought to determine the effect of social isolation (separation from the flock) in a novel environment with and without a conspecific present on the adrenocortical activity of paired and unpaired individuals of this species. With regard to paired birds, we hypothesized that the presence of the mate during isolation from the group would act as a social buffer against the stressful effects of isolation. We observed that 10 but not 30 minutes of social isolation resulted in elevated concentrations of corticosterone in unpaired and paired male zebra finches in comparison to baseline concentrations of corticosterone. Furthermore, the presence of a mate during isolation in a novel environment did not have a buffering effect against increases in corticosterone concentrations. Additionally, to compare concentrations of corticosterone in response to isolation (in a novel environment) to a previously well-established stressor, we subjected groups of birds to restraint. We observed that 10 or 30 minutes of restraint led to significantly higher concentrations of corticosterone as compared to baseline. Finally, to rule out the possibility that merely handling a bird would result in significantly elevated concentrations of corticosterone as compared to baseline samples, we measured corticosterone concentrations 10 or 30 minutes after handling involving capture and release only. Our results suggest that handling alone might have contributed to the elevation of corticosterone in birds exposed to 10 minutes but not 30 minutes of restraint. Handling by itself did not account, however, for the elevated corticosterone in birds socially isolated for 10 minutes.Hormones and Behavior 06/2011; 60(3):233-8. · 4.51 Impact Factor
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ABSTRACT: KRAS mutations have been extensively investigated as predictive biomarkers for treatment of advanced colorectal cancer with the anti-epidermal growth factor receptor (EGFR) antibodies cetuximab and panitumumab. To summarize whether KRAS mutation status modifies effects of anti-EGFR-based treatments for patients with advanced colorectal cancer and whether KRAS status predicts clinical outcomes among such patients. MEDLINE and 2 curated genetics databases (through 24 March 2010) were searched for observational studies. MEDLINE, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and the Database of Abstracts of Reviews of Effects (through 1 September 2010) were searched for randomized, controlled trials. No search was restricted by language. Three reviewers screened titles and abstracts to identify published studies assessing KRAS mutations as predictors of overall and progression-free survival or treatment failure for patients who received anti-EGFR-based therapy for metastatic colorectal cancer. Three investigators extracted data on population and study-design characteristics, including quality items, and on outcomes of interest. Random-effects meta-analyses were done on nonoverlapping studies. In 4 reanalyses of randomized trials of anti-EGFR-based therapy versus best supportive care or cytotoxic chemotherapy, no significant benefit was found for overall or progression-free survival from anti-EGFR-based treatment among KRAS-positive patients (hazard ratio [HR], 1.0). However, evidence favors anti-EGFR therapy among KRAS wild-type patients; the relative HR across KRAS-positive and wild-type patients was 1.30 (95% CI, 0.95 to 1.78) for overall survival and 2.22 (CI, 1.74 to 2.84) for progression-free survival by random-effects meta-analysis. In 13 cohorts of patients who received anti-EGFR antibodies, the summary HR for overall survival was 1.79 (CI, 1.48 to 2.17), with better survival in wild-type patients. The corresponding HR for progression-free survival was 2.11 (CI, 1.74 to 2.55 [16 cohorts]). In random-effects bivariate meta-analysis of 22 studies, the summary sensitivity of KRAS mutations for predicting lack of response was 0.49 (CI, 0.43 to 0.55), and summary specificity was 0.93 (CI, 0.87 to 0.97). Limited evidence from randomized studies exists. Patient-level data are needed to assess modifiers of the mutation-by-treatment interaction. Publication bias could be a concern. KRAS mutations are consistently associated with reduced overall and progression-free survival and increased treatment failure rates among patients with advanced colorectal cancer treated with anti-EGFR antibodies. Agency for Healthcare Research and Quality.Annals of internal medicine 01/2011; 154(1):37-49. · 16.10 Impact Factor
KRAS mutational status assessment in patients with
metastatic colorectal cancer: are the clinical implications
M. HEBBAR, md, phd, Department of Medical Oncology, University Hospital, Lille, P. FOURNIER, md, Depart-
ment of Medical Oncology, University Hospital, Lille & O. ROMANO, md, Department of Medical Oncology,
University Hospital, Lille, France
HEBBAR M., FOURNIER P. & ROMANO O. (2010) European Journal of Cancer Care 19, 167–171
KRAS mutational status assessment in patients with metastatic colorectal cancer: are the clinical implications
The CRYSTAL study demonstrated an advantage in terms of objective response and progression-free survival
for the FOLFIRI–cetuximab combination compared with first-line FOLFIRI for patients with metastatic
colorectal cancer. The results of an ancillary biological study with screening for a KRAS gene mutation in 540
patients were reported at the 2008 American Society of Clinical Oncology congress. The analysis confirmed
the value of adding cetuximab only in the absence of KRAS mutation. These results led to recommend
restriction of the use of cetuximab in Europe to patients with a tumour bearing wild-type KRAS. How should
this apparent simplification be integrated into clinical practice? The FOLFIRI–cetuximab combination is
certainly a useful supplementary first-line option although its place in relation to other high-dose regimens
(high-dose FOLFIRI, FOLFOXIRI or FOLFOX-7), conventional chemotherapy plus bevacizumab, or even a
fluoropyrimidine alone in the case of unresectable metastases, has yet to be specified. For subsequent lines, no
study has prospectively assessed the value of the chemotherapy–anti-epidermal growth factor receptor com-
bination as a function of KRAS status. Should the absence of objective response constantly observed in
retrospective analyses in patients with a tumour presenting a KRAS mutation definitively exclude these
patients while stable disease (and potentially a slight gain in survival) may be obtained?
Keywords: colorectal cancer, cetuximab, panitumumab, KRAS mutations.
In the context of its initial marketing authorisation (June
2004), cetuximab was indicated in patients with meta-
static colorectal cancer (CRC) in combination with irino-
tecan, after failure of irinotecan-based chemotherapy
and in the presence of tumour expression of the epidermal
growth factor receptor (EGFR) demonstrated by immuno-
histochemistry. This indication was based on the original
study (BOND) and the fact that, experimentally, cetux-
imab appeared to restore tumour sensitivity to irinotecan
(Prewett et al. 2002; Xu & Villalona-Calero 2002; Cun-
ningham et al. 2004). Cetuximab was the first targeted
therapy validated for the treatment of colorectal cancer
and its use was based on solid biological data. However, it
was rapidly observed that preliminary screening for
tumour expression of EGFR had no practical value
because similar tumour response rates were described in
patients with negative EGFR expression (Chung et al.
2005; Hebbar et al. 2006). Screening for EGFR expression
is therefore no longer explicitly required, which means
that a reliable predictive factor of response to cetuximab is
no longer available. The intensity of the acneiform skin
Correspondence address: Prof. Mohamed Hebbar, Unité d’Oncologie Médi-
cale, Centre Hospitalo-Universitaire, 1 rue Michel Polonovski, 59037 Lille,
France (e-mail: email@example.com).
Accepted 1 February 2009
European Journal of Cancer Care, 2010, 19, 167–171
© 2009 Blackwell Publishing Ltd
reaction certainly has a predictive value, but this factor
obviously cannot be assessed before starting treatment.
A better understanding of the signalling pathways
resulting from EGFR activation has emphasised the role of
the KRAS gene. This gene is mutant in 30–40% of col-
orectal cancers and several retrospective studies have indi-
cated the absence of tumour response in patients treated
with cetuximab-irinotecan when the tumour presents a
KRAS mutation (Lièvre et al. 2006; Di Fioré et al. 2007;
Lièvre et al. 2008). An ancillary biological study to the
trial evaluating another anti-EGFR antibody, panitu-
mumab, in multitreated patients confirmed the absence of
benefit in patients with a tumour with a KRAS mutation
(Amado et al. 2008). This logically led to restriction of the
marketing authorisation for panitumumab to patients
with a tumour presenting wild-type KRAS. Similar data
concerning cetuximab were eagerly awaited and were
KRAS AND EFFICACY OF CETUXIMAB:
Progress in gastrointestinal oncology at the 2008 Ameri-
can Society of Clinical Oncology (ASCO) congress was
dominated by data concerning the response to cetuximab
as a function of KRAS mutation status in the first-line
management of patients with metastatic CRC (CRYSTAL
study) (Van Cutsem et al. ASCO 2008a,b). This phase III
study compared conventional FOLFIRI chemotherapy
with the FOLFIRI chemotherapy combined with cetux-
imab. Preliminary efficacy results were presented at
ASCO 2007 (Van Cutsem et al. 2007). In 1198 patients of
the Intent-To-Treat population, the objective response
rate was significantly higher with addition of cetuximab
(47% vs. 39%, P = 0.038), and the progression-free
survival was also longer (8.9 vs. 8 months, P = 0.048).
Furthermore, more secondary resections of metastases
were performed in the FOLFIRI-cetuximab arm (4.3% vs.
1.5%, P = 0.0034).
For the recently presented study of KRAS mutations,
540 tumour blocks were used for DNA extraction and
PCR detection of the main known mutations (codons 12
and 13). The population of selected patients was appar-
ently not biased: tumour and demographic characteristics
were similar to those of the total population. The
same differences in terms of objective responses and
progression-free survival were observed between the two
treatment arms. The KRAS gene was mutant in 192 of 540
patients (35.6%). This analysis confirmed a significant
difference in terms of tumour response and progression-
free survival as a function of KRAS status. In patients with
wild-type KRAS (348 patients), the objective response rate
was improved by addition of cetuximab to FOLFIRI (59%
vs. 43%, P = 0.0025). Progression-free survival was also
significantly increased from 8.7 to 9.9 months (P = 0.017).
On the other hand, in 192 patients with KRAS mutation,
cetuximab did not provide any benefit compared with
chemotherapy alone in terms of either response rate (36%
vs. 40%, P = 0.46) or progression-free survival (7.6 vs. 8.1
months, P = 0.47). Note that the efficacy of chemotherapy
alone did not appear to be affected by KRAS status (objec-
tive response rate: 43% vs. 40%, progression-free survival:
8.7 vs. 8.1 months, in the absence and in the presence of
KRAS mutation respectively).
Very recently, convergent results were reported in Bar-
celona concerning the use of cetuximab monotherapy in
patients pretreated by oxaliplatin and irinotecan. These
results were derived from a retrospective ancillary biologi-
cal analysis of trial NCIC-CTC CO.17 comparing cetux-
imab with symptomatic treatment (Jonker et al. 2007).
Analysis of KRAS status was performed on 394 tumour
samples and a mutation was detected in 42% of cases
(Karapetis et al. 2008). Cetuximab doubled the overall
median survival in the absence of KRAS mutation (9.5 vs.
4.8 months, P < 10-4). In contrast, in the presence of KRAS
mutation, addition of cetuximab did not provide any sur-
vival benefit (4.5 months in the two arms). Also note that
the presence of a KRAS mutation had no intrinsic prognos-
In the light of all of these results, the CHMP (Commit-
tee for Medicinal Products for Human Use; the European
Medicines Agency scientific committee) now recom-
mends the use of cetuximab for the treatment of patients
with metastatic CRC expressing EGFR and wild-type
KRAS. This applies to the cetuximab–chemotherapy com-
bination and to cetuximab monotherapy in patients pre-
treated by irinotecan and oxaliplatin and in the case of
intolerance of irinotecan.
Several ongoing trials evaluating anti-EGFR antibodies
must be amended in both the palliative and adjuvant set-
tings, for example:
•C80405 (FOLFIRI or FOLFOX + cetuximab and/or beva-
cizumab as first-line therapy)
•S 0600 (irinotecan-based chemotherapy + cetuximab
and/or bevacizumab as first-line therapy)
•No 147 and PETACC 8 (FOLFOX ? cetuximab as adju-
Finally, these results encourage the evaluation of other
targeted therapies in patients with a tumour presenting a
KRAS mutation: for example, inhibitors acting on the
PI3K pathway or downstream to KRAS. In this last group,
HEBBAR et al.
© 2009 Blackwell Publishing Ltd 168
– sorafenib, a multitarget inhibitor especially acting on
raf-kinases must be evaluated in combination with irino-
tecan (NEXIRI study).
CRITICAL ANALYSIS, PRACTICAL
The results of the CRYSTAL study appear to be convinc-
ing: they validate the value of first-line cetuximab and
confirm that the efficacy of this molecule is determined
by KRAS mutation status. They are also corroborated
(at least in patients with wild-type KRAS, as some
effects of the FOLFOX–cetuximab combination need to
be clarified in patients with KRAS mutation) by the
results of the phase II OPUS study, comparing first-line
FOLFOX versus FOLFOX–cetuximab (Bokemeyer et al.
The CRYSTAL study provides a supplementary first-
line treatment option. The FOLFIRI–cetuximab combi-
nation could be particularly useful when bevacizumab is
contraindicated but also in patients with metastases con-
fined to the liver which could be made resectable in the
case of a major tumour response. The advantage of this
approach would be to avoid the operative risks inherent
to the use of bevacizumab. However, although the rate
of secondary resection of metastases is significantly
higher in the FOLFIRI-cetuximab arm, it nevertheless
remains very low (less than 30 out of 600 patients).
Other studies have reported higher secondary resection
rates with irinotecan- or oxaliplatin-based chemotherapy
alone (Adam et al. 2004). ‘Intensified’ treatment regi-
mens, such as high-dose FOLFIRI or FOLFIRINOX also
appear to be promising in the context of secondary resec-
tion (Ychou et al. 2002; Duffour et al. 2007; Ducreux
et al. 2008; Rivoire et al. 2008). The potential advantages
of these regimens compared with FOLFIRI–cetuximab
would be their lower cost and the fact that they do not
require preliminary evaluation of KRAS status. Further-
more, should a FOLFIRI–cetuximab combination really
be proposed in the great majority of patients with
metastases who will obviously never be resected, bearing
in mind that this combination requires preliminary
evaluation of KRAS status? Globally, although statisti-
observed in CRYSTAL is modest (gain of 0.9 months for
the overall population, 1.2 months for patients with
wild-type KRAS). Moreover, the overall survival was not
significantly increased by the use of cetuximab in the
whole population, as well as in the patients with wild-
type KRAS status (2008 ESMO meeting). Although the
studies are not comparable, it must be remembered that
trials evaluating first-line bevacizumab indicated higher
survival gains (11.2 months of progression-free survival
and 28 months of overall survival in the BICC-C study
in combination with FOLFIRI, for example). The limited
benefit provided by first-line cetuximab may suggest that
this molecule could be safely reserved to subsequent
lines of treatment, after failure of chemotherapy. Various
studies have shown that the efficacy of cetuximab is
maintained with successive lines of treatment (Lenz
et al. 2006; Hebbar et al. 2007). Consequently, first-line
use of cetuximab in unselected patients could deprive
patients of a subsequent potentially effective treatment
option. Finally, recent strategic studies have shown that,
when there is no hope of resection of metastases, it is
perfectly legitimate to start treatment with a fluoropyri-
midine alone (Bouché et al. 2007; Koopman et al. 2007;
Seymour et al. 2007; Di Fioré et al. 2008).
This raises the following question: if the use of cetux-
imab is envisaged beyond the first line (initial marketing
authorisation), should KRAS status also be evaluated?
Several studieshave demonstrated
objective response in patients treated with irinotecan-
cetuximab after failure of irinotecan, when the tumour
presents a KRAS mutation (Lièvre et al. 2006; Di Fioré
et al.2007;Lièvreet al.2008).However,allofthesestudies
were retrospective and the endpoint evaluated (objective
advanced stage of disease. The most convincing data con-
cerning the impact of KRAS status in pretreated patients
were obtained for panitumumab and cetuximab, but
administered as monotherapy, as indicated above.
In the absence of a specific prospective study, it is
unclear whether pretreated patients with a KRAS muta-
tion can derive any benefit from a chemotherapy–anti-
EGFR combination. In a recent meta-analysis by Di Fioré
on 281 patients treated with the irinotecan–cetuximab
combination, although no objective response was ob-
served in patients with a tumour presenting a KRAS
mutation, stable disease was nevertheless observed in
41% of cases, and the median progression-free survival
was 2.7 months (Di Fioré et al. 2008). A phase II pro-
panitumumab combination in 102 patients following
failure of FOLFOX–bevacizumab (Cohn et al. 2008). The
response rate was 21% although it is usually less than 5%
with second-line irinotecan after failure of oxaliplatin
(Tournigand et al. 2004; Sobrero et al. 2008). This result
clearly suggests a gain provided by the addition of the
anti-EGFR. The response rate was also not influenced by
the tumour KRAS status: 22% of responses in the absence
of mutation and 19% in the presence of a mutation.
the absence of
evaluated the FOLFIRI–
KRAS status in metastatic colorectal cancer
© 2009 Blackwell Publishing Ltd 169
The results of the CRYSTAL study on the impact of KRAS
mutation status were eagerly awaited. These results
confirm the impression that cetuximab is especially
useful in the absence of KRAS mutation. This was con-
firmed for cetuximab monotherapy in pretreated patients.
These results led EMEA to restrict the use of cetuximab to
patients with a tumour with wild-type KRAS. At first
sight, this represents a definite progress and corresponds
to the strategy of tailored use of targeted therapies. It may
therefore be perfectly relevant to propose first-line treat-
ment with an irinotecan–cetuximab combination in a
patient with a tumour with wild-type KRAS when a major
tumour response would allow resection of metastases.
However, the actual place of this combination compared
with other regimens using bevacizumab, high-dose che-
motherapy, or even a 5-FU-irinotecan-oxaliplatin combi-
nation needs to be defined. After first line, several
retrospective studies have shown that an objective
tumour response is illusory in patients with a KRAS
mutation, but what about disease control and survival?
Isn’t there a risk of depriving patients who have already
received all available chemotherapies and bevacizumab of
an even modest survival gain? Only a specific, prospective
evaluation of the impact of KRAS status on the efficacy of
a chemotherapy–anti-EGFR combination in pretreated
patients would be able to answer this question. These
uncertainties mean that the place of evaluation of KRAS
status in clinical practice has yet to be defined. Further-
more, this laboratory test is only at the stage of evaluation
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