Personalized Therapy
Arrives for Patients with Colorectal
Cancer
by David W. Sharp
Earlier this year the American Society of
Clinical Oncology (ASCO) offered as a "provisional
clinical opinion" the statement that "all patients with
metastatic colon cancer should have their tumors tested
for KRAS mutations" (J. Clin. Oncol.,
27[12]: 2091-6, 2009). Others have said much the same
thing—for example, it should be "standard
practice" to restrict colon-cancer treatment targeted
at the epidermal growth factor receptor (EGFR) to
patients whose tumors test positive for wild-type
(non-mutated) KRAS (D.Z. Chang, et
al., J. Hematol. Oncol., 2:18,
2009).
Molecular Location on
chromosome 12: base pairs
25,249,446 to
25,295,120.
The National Comprehensive Cancer Network clinical
guideline on colon cancer reflects this change, too; in
the U.K. the documentation for a clinical trial of
chemotherapy with or without the EGFR-targeting drug
cetuximab that is seeking to recruit patients with
advanced bowel cancers is excluding those with
KRAS mutations; official labelling for
cetuximab and another drug that targets EGFR has lately
been altered to reflect the change in recommended
practice. Furthermore, KRAS tests are being
widely marketed. Three papers in the Journal of
Clinical Oncology that are in the Top Ten (#8) or
hover outside that list (S. Khambata-Ford, et
al., 25[22]: 3230-7, 2007; total cites 174, latest
count 36, at #13; and A. Lievre, et al.,
26[3]: 374-9, 2008; total cites 139, latest count 36,
at #14) are being widely quoted because the data in
them contribute significantly to accumulating evidence
for this "step toward personalized medicine for
patients with colorectal cancer" (Y. Jiang, et
al., Cancer, 115[16]: 3609-17, 2009). The
most recent of this trio appeared in April, 2008, but
the evidence keeps rolling in—see, for example,
C.S Karapetis, et al., from October of the
same year (New Engl. J. Med., 359[17]:
1757-65, 2008).
KRAS is a gene, the human homolog of the
Kirsten rat sarcoma-2 virus oncogene, that is linked
with cellular signalling pathways, including those
involving EGFR itself. The drugs active against EGFR
include cetuximab and panitumumab. Dr. Rafael G. Amado
and colleagues (#8) tested for KRAS mutations
as part of a randomized trial comparing panitumumab and
best supporting care in patients with metastatic colon
cancer. Any effect of the drug was limited to those
with wild-type KRAS. In #13 the drug was
cetuximab and other markers (two EGFR ligands) were
studied but the result for KRAS was similar to
#8’s: patients whose tumors lacked KRAS
mutations had significantly greater disease control
from cetuximab. And a similar message emerged from the
third paper (#14).
Might possession of a mutated KRAS by itself
contribute to a poorer outlook for patients with
advanced bowel cancer, irrespective of any treatment
aimed at EGFR? Seemingly not. A presentation at this
year’s ASCO meeting (C. Fuchs, et al.,
J. Clin. Oncol., 27[15s]: abstr 4037, 2009)
drew on data from a chemotherapy trial starting 10
years ago and not involving EGFR-targeting agents.
Possession of wild-type as opposed to mutated
KRAS had no effect on disease-free or overall
patient survival. A poster at a symposium on
gastrointestinal cancers held during ASCO 2009 (V.
Shankaran, et al. ) provided an answer to a
different question: Since KRAS testing is not
cheap and since drugs like cetuximab are expensive,
does a policy of not giving such drugs to those whose
tumors are wild-type KRAS make sense in terms
of economics as well as clinically? It seems that the
cost of KRAS testing incident cases (estimated
at $13 million a year for the US) is very much less
than the savings made by not giving drugs predicted to
be of no benefit to the recipient. A health economic
analysis of a large Canadian trial, noting the daunting
added costs involved when cetuximab is added to best
supportive care alone, found the impact much reduced
for patients with wild-type KRAS (N. Mittmann,
et al., J. Natl. Cancer Inst.,
101[17]: 1182-92, 2009).
A former deputy editor of The
Lancet, Mr. David W. Sharp, M.A. (Cambridge) is a
freelance writer living in Minchinhampton,
U.K.
Medicine
Top 10
Papers
Rank
Paper
Citations
This Period
(May-Jun
09)
Rank
Last Period
(Mar-Apr
09)
1
The ACCORD Study
Group (H.C.
Gerstein, et
al.), "Effects
of intensive
glucose lowering in
type
2 diabetes,"
New Engl. J.
Med., 358(23):
2545-59, 12 June
2008. [Writing
Group: 10 U.S. and
Canadian
institutions]
*311IJ
87
1
2
The ADVANCE
Collaborative Group
(A. Patel, et
al.),
"Intensive blood
glucose control and
vascular outcomes
in patients with
type 2 diabetes,"
New Engl. J.
Med., 358(24):
2560-72, 12 June
2008. [Writing
Group: 18
institutions
worldwide] *311IJ
69
3
3
J. Yu, et
al., "Induced
pluripotent
stem
cell lines
derived from
human somatic
cells,"
Science,
318(5858):
1917-20, 21
December 2007.
[Genome Ctr.
Wisconsin,
Madison; U.
Wisconsin,
Madison] *243HE
68
2
4
The ONTARGET
Investigators (S.
Yusuf, et
al.),
"Telmisartan,
ramipril, or both
in patients at high
risk for vascular
events," New
Engl. J. Med.,
358(15): 1547-59,
10 April 2008.
[Writing committee:
5 institutions
worldwide] *285NK
57
†
5
B. Escudier, et
al.,
"Bevacizumab plus
interferon alfa-2a
for treatment of
metastatic renal
cell carcinoma: a
randomized,
double-blind phase
III trial,"
Lancet,
370(9605): 2103-11,
December-January
2007. [15
institutions
worldwide] *247DY
52
†
6
R.R. Holman, et
al., "10-year
follow-up of
intensive glucose
control in type 2
diabetes," New
Engl. J. Med.,
359(15): 1577-89, 9
October 2008. [6
U.K. institutions]
*358FS
49
8
7
J.M. Llovet, et
al.,
"Sorafenib in
advanced
hepatocellular
carcinoma," New
Engl. J. Med.,
359(4): 378-90, 24
July 2008. [22
institutions
worldwide] *329FK
45
†
8
R.G. Amado, et
al.,
"Wild-type
KRAS is
required for
panitumumab
efficacy in
patients with
metastatic
colorectal cancer,"
J. Clin.
Oncol.,
26(10): 1626-34, 1
April 2008. [Amgen,
Thousand Oaks, CA;
Ghent Univ. Hosp.,
Belgium; Univ.
Hosp. Gasthuisberg,
Leuven, Belgium;
Ospedale Niguarda
Ca’ Granda,
Milan, Italy]
*281WY
44
†
9
K. Miller, et
al.,
"Paclitaxel plus
bevacizumab versus
paclitaxel alone
for metastatic
breast
cancer,"
New Engl.
J. Med.,
357(26):
2666-76, 27
December 2007.
[9 U.S. and
Canadian
institutions]
*245UO
42
10
10
E.S. Chung, et
al., "Results
of the Predictors
of Response to CRT
(PROSPECT) trial,"
Circulation,
117(20): 2608-16,
20 May 2008. [13
institutions
worldwide] *303PQ