original articles
Annals of Oncology
Annals of Oncology 26: 2092–2097, 2015
doi:10.1093/annonc/mdv290
Published online 7 July 2015
BRAF codons 594 and 596 mutations identify a new
molecular subtype of metastatic colorectal cancer
at favorable prognosis
C. Cremolini1, M. Di Bartolomeo2, A. Amatu3, C. Antoniotti1, R. Moretto1, R. Berenato2, F. Perrone4,
E. Tamborini4, G. Aprile5, S. Lonardi6, A. Sartore-Bianchi3, G. Fontanini7, M. Milione4, C. Lauricella8,
S. Siena3,8, A. Falcone1, F. de Braud2, F. Loupakis1 & F. Pietrantonio2*
1
Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa; 2Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan;
S. C. Oncologia Falck, Niguarda Cancer Center, Ospedale Niguarda Ca’ Granda, Milano; 4Department of Pathology and Molecular Biology, Fondazione IRCCS Istituto
Nazionale dei Tumori, Milan; 5Department of Medical Oncology, Azienda Ospedaliero-Universitaria, Udine; 6UOC Oncologia Medica 1, Istituto Oncologico Veneto–IRCCS,
Padova; 7Department of Surgery, Division of Pathology, University of Pisa, Pisa; 8University of Milan, Milan, Italy
3
Received 12 May 2015; revised 30 June 2015; accepted 1 July 2015
Background: While the negative prognostic role of BRAF V600E mutation in metastatic colorectal cancer (mCRC) is
well established, the impact of BRAF codons 594 and 596 mutations, occurring in <1% of CRCs, is completely unknown.
The present work aims to describe clinical, pathological and molecular features and prognosis of BRAF codons 594 and
596 mutant mCRCs, compared with BRAF V600E mutant and wild-type ones.
Patients and methods: Patients treated for mCRC at three Italian Institutions between October 2006 and October 2014,
with available KRAS and NRAS codon 12, 13, 59, 61, 117 and 146 and BRAF codon 594, 596 and 600 mutational status, as
detected by means of direct sequencing or matrix assisted laser desorption ionization time-of-flight MassArray, were included.
Results: Ten patients bearing BRAF codons 594 or 596 mutated tumors were identified and compared with 77 and 542
patients bearing BRAF V600E mutated and BRAF wild-type tumors, respectively. While BRAF V600E mutated tumors
were more frequently right-sided, mucinous and with peritoneal spread, BRAF 594 or 596 mutated were more frequently
rectal, nonmucinous and with no peritoneal spread. All BRAF 594 or 596 mutated tumors were microsatellite stable.
Patients with BRAF codons 594 or 596 mutated tumors had markedly longer overall survival (OS) when compared with
BRAF V600E mutated [median OS: 62.0 versus 12.6 months; hazard ratio: 0.36 (95% confidence interval 0.20–0.64),
P = 0.002], both at univariate and multivariate analyses.
Conclusions: BRAF codon 594 or 596 mutated mCRCs are different from BRAF V600E ones in terms of molecular features, pathological characteristics and clinical outcome. This is consistent with preclinical evidences of a kinase inactivating effect of these mutations. The role of CRAF in transducing the intracellular signal downstream BRAF 594 or 596
mutated proteins opens the way to further preclinical investigation.
Key words: colorectal cancer, BRAF, codons 594 and 596, prognosis
introduction
BRAF testing allows to identify a subgroup of metastatic colorectal
cancer (mCRC) patients (i.e. those harboring V600E mutation)
who derive modest benefit from standard treatments and have extremely poor prognosis [1–3]. BRAF V600E mutated mCRC share
peculiar clinical and pathological characteristics: they are more frequent in women than men; are often right-sided; present mucinous histology and microsatellite instability (MSI high); spread to
*Correspondence to: Dr Filippo Pietrantonio, Department of Medical Oncology,
Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy. Tel:
+39-02-2390-3807; Fax: +39-02-2390-2149; E-mail: fi[email protected]
lymph nodes and peritoneum [4–6]. When liver metastases are
radically resected, BRAF V600E mutated tumors often relapse
early, due to the occurrence of extrahepatic lesions [7, 8].
In this patients’ subgroup, first-line doublets plus a monoclonal antibody achieved unsatisfactory outcomes [2] and there is
growing evidence on BRAF V600E mutation as a biomarker of
resistance to anti-epidermal growth factor receptor (EGFR)
monoclonal antibodies [9, 10]. First-line chemotherapy with
FOLFOXIRI plus bevacizumab [11, 12] has been recently shown
to provide encouraging results in this subgroup [13].
Based on these considerations and according to the recommendations of international clinical guidelines [14, 15], BRAF
testing has entered the clinical practice worldwide.
© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: [email protected].
original articles
Annals of Oncology
Direct sequencing has been the preferred technique to detect
BRAF mutations for long and is still widely used in many laboratories. The portion of BRAF gene that is amplified and then
sequenced also includes codons 594 and 596, mapping close to
codon 600 and mutated in <1% of CRCs [16]. Recently, more accurate and sensitive technologies have been developed, so that
assays able to provide a comprehensive overview of genomic alterations that may drive clinical decisions are currently adopted in molecular laboratories [17]. These technologies often include also the
evaluation of BRAF mutations in codons 594 and 596, beyond
codon 600.
Nevertheless, the clinical impact of these mutations is completely unknown, so that oncologists frequently face the dilemma
of how to interpret these findings and how to properly translate
this information into clinical practice. Do these mutations share
with BRAF V600E mutation the same pathogenic effect? Do
BRAF 594 or 596 mutated tumors share with BRAF V600E
mutated the same clinical and pathological characteristics? Do
they confer the same dismal prognosis?
We collected samples and clinical data from patients bearing
these rare alterations and compared their clinical and pathological characteristics as well as their clinical outcome with those
of patients bearing BRAF V600E mutated and BRAF wild-type
mCRCs.
patients and methods
patients and molecular analyses
We retrospectively collected clinical data from mCRC patients treated at
three Italian Institutions between October 2006 and October 2014.
Tumors’ blocks from primary tumors (80%) and/or paired metastases (20%)
were first analyzed for KRAS and NRAS codon 12, 13, 59, 61, 117 and 146 and
BRAF codon 594, 596 and 600 status by means of direct sequencing or matrix
assisted laser desorption ionization time-of-flight MassArray® (Sequenom, San
Diego, CA). All samples were from treatment naïve patients. Heterogeneity
Score (HS) was calculated as previously described [18]. Next-generation sequencing of 50 genes’ hotspot regions included in the Hotspot Cancer Panel v2 (Life
Technologies) was then carried out by using the Ion Torrent Personal Genome
Machine platform (Life Technologies) [19] in BRAF codon 594 or 596 mutated
samples. MSI status was assessed as previously described [20].
statistics
Fisher’s exact test or χ 2 test was used when appropriate to compare clinical
and biological features according to BRAF mutational status.
Overall survival (OS) was defined as the time from the diagnosis of metastatic disease to death due to any cause. OS analysis was determined according to the Kaplan–Meier method and survival curves were compared using
the log-rank test. Statistical significance was set at P = 0.05 for a bilateral test.
The correlation of mutational status and clinical and pathological characteristics with survival was assessed in univariate analyses. Cox proportional
hazard model was adopted in the multivariate analysis, including as covariates variables significantly correlated with survival in the univariate analyses.
All analyses were carried out by means of MedCalc Software (Ostend,
Belgium).
results
Ten mCRC patients bearing mutations in BRAF codons 594
(N = 9) or 596 (N = 1) were identified and their characteristics
Volume 26 | No. 10 | October 2015
and survivals were compared with those of 77 patients bearing
BRAF V600E mutation and 542 patients with BRAF wild-type
tumors treated in the same period. RAS mutations were found
in 305 (57.3%) of 532 BRAF wild-type tumors evaluable for RAS
Table 1. Patients’ characteristics according to BRAF mutational
status
Characteristics
BRAF
wild-type
(N = 542)
n (%)
Sex
Female
206 (38)
Male
336 (62)
Age
Median
66
Range
28–92
ECOG PS
0
313 (72)
1–2
121 (28)
NA
108
Primary tumor site
Right colon
169 (31)
Left colon
215 (40)
Rectum
158 (29)
Mucinous histology
Yes
89 (19)
No
368 (81)
NA
85
pT
1–2
53 (13)
3–4
359 (87)
Tx
130
pN
0
102 (25)
1–2
306 (75)
Nx
134
Time to metastases
Synchronous 374 (69)
Metachronous 168 (31)
Number of metastases
1
346 (64)
>1
196 (36)
Lung metastases
Yes
135 (25)
No
407 (75)
Nodes metastases
Yes
99 (18)
No
443 (82)
Peritoneal metastases
Yes
111 (20)
No
431 (80)
BRAF
V600E
mut
(N = 77)
n (%)
BRAF 594
or 596
mut
(N = 10)
n (%)
Pa
Pb
44 (57)
33 (43)
8 (80)
2 (20)
<0.001 0.304
65
28–86
67
44–83
0.986 0.893
45 (67)
22 (33)
10
8 (80)
2 (20)
–
0.591 0.716
49 (64)
11 (14)
17 (22)
1 (10)
2 (20)
7 (70)
<0.001 0.003
32 (45)
39 (55)
6
2 (20)
8 (80)
–
<0.001 0.180
4 (6)
58 (94)
15
3 (38)
5 (62)
2
0.035 0.028
12 (19)
50 (81)
15
5 (62)
3 (38)
2
0.029 0.017
57 (74)
20 (26)
4 (40)
6 (60)
0.089 0.059
41 (53)
36 (47)
7 (70)
3 (30)
0.177 0.501
17 (22)
60 (78)
1 (10)
9 (90)
0.490 0.680
28 (36)
49 (64)
4 (40)
6 (60)
<0.001 1.000
27 (35)
50 (65)
0 (0)
10 (100)
0.004 0.028
Bold values indicate significance level set at 0.05.
a
Comparison of the three groups (BRAF wild-type versus BRAF V600E
mut versus BRAF 594 or 596 mut).
b
Comparison of BRAF V600E mut versus BRAF 594 or 596 mut.
doi:10.1093/annonc/mdv290 | 
original articles
Annals of Oncology
peritoneal metastases in 35% of cases, peritoneal involvement was
never reported in BRAF 594 or 596 mutated (P = 0.028).
When compared with BRAF wild-type tumors, BRAF 594 or
596 mutated tumors occurred more frequently in females (80%
versus 38%, P = 0.016), and in rectum (70% versus 29%, P =
0.020), and with metachronous presentations (60% versus 31%,
P = 0.080).
status and in 2 (20%) of 10 BRAF 594 or 596 mutated tumors.
No concurrent RAS and BRAF V600E mutations were found.
clinical and pathological characteristics
As shown in Table 1, baseline characteristics of BRAF 594 or
596 mutated tumors were different when compared with BRAF
V600E mutated. In particular, while BRAF V600E mutated
tumors were more frequently right-sided (64%), BRAF 594 or
596 mutated were more frequently rectal (70%, P = 0.003).
Mucinous histology was reported in the 45% of BRAF V600E
mutated tumors, when compared with the 20% of BRAF 594 or
596 mutated (P = 0.180). With regard to the pattern of metastatic
spread, while BRAF V600E mutated tumors presented with
MSI and next-generation sequencing analyses
Notably, all BRAF 594 or 596 mutated samples were classified
as microsatellite stable. At the next-generation sequencing of
50 genes’ hotspot regions, as above mentioned, we found that 2
of 10 BRAF 594 and 596 mutated samples had concomitant
non-exon 2 KRAS mutations, namely a NRAS G13V and a
KRAS A146T, with 10% and 20% of mutant alleles, respectively
(22% and 33% when normalizing for neoplastic cells content).
None of BRAF V600E mutated samples displayed other RAS
mutations (P = 0.012) (Table 2). Notably, the HS for BRAF 594
or 596 mutations was significantly lower in samples bearing
other alterations in the EGFR axis (RAS or PTEN mutations)
than in samples not bearing other mutations (P = 0.034).
Table 2. Genomic alterations detected by Ion Torrent in BRAF 594
or 596 mutated samples
Patient ID
Genomic alterations
1-1
1-2
1-3
1-4
2-5
2-6
2-7
2-8
3-9
3-10
BRAF D594G
BRAF D594G: TP53 R175H; del CDKN2A exon 2
BRAF D594G
BRAF D594G; TP53 C135W
BRAF D594N
BRAF D594A
BRAF D594G; TP53 R175H; APC K1370 stop
BRAF G596R; KRAS A146T
BRAF D594N; NRAS G13V; TP53 R175H
BRAF D594G; PTEN D107Y
100
BRAF mutations and prognosis
When looking at OS results, at a median follow-up of 45.6
months, the poor prognosis of patients bearing BRAF V600E
mutated tumors was confirmed {median OS: 12.6 versus 35.9
months in BRAF wild-type; hazard ratio (HR): 5.70 [95% confidence interval (CI) 3.74–8.69], P < 0.001} (Figure 1). Conversely,
BRAF 594 or 596 mutated patients showed a trend toward longer
OS when compared with BRAF wild-type [62.0 versus 35.9 months;
BRAF 594/596 mut (N = 10) – median OS: 62.0 mos
BRAF wt (N = 540) – median OS: 35.9 mos
BRAF V600E mut (N = 77) – median OS: 12.6 mos
% Overall survival
75
Log-rank test, P < 0.001
50
25
0
0
25
50
100
75
125
150
175
Months
HR for death according to BRAF mutational status:
HR
0.36 [0.20–0.64]
BRAF 594/596 vs BRAF V600E
BRAF 594/596 vs BRAF wt
0.55 [0.29–1.05]
5.70 [3.74–8.69]
BRAF V600E vs BRAF wt
*Statistically significant, OS = overall survival, wt = wild type, HR = hazard ratio
p-value
0.002*
0.081
<0.001*
Figure 1. Kaplan–Meier estimates of overall survival according to BRAF status.
 | Cremolini et al.
Volume 26 | No. 10 | October 2015
original articles
Annals of Oncology
HR: 0.55 (95% CI 0.29–1.05), P = 0.081] and a significantly longer
OS than BRAF V600E mutated [62.0 versus 12.6 months; HR:
0.36 (95% CI 0.20–0.64), P = 0.002]. In the multivariable model
(Table 3) including other covariates significantly associated with
OS ( performance status, primary tumor site, time to metastases
and number of metastatic sites), BRAF 594 or 596 mutations
were still associated with longer OS than BRAF V600E mutation
[HR: 0.21 (95% CI 0.07–0.64), P = 0.006].
Systemic and locoregional treatments delivered to patients
bearing BRAF 594 or 596 mutated tumors are summarized in
Table 4. Three of four patients treated with upfront chemotherapy plus cetuximab achieved partial response.
Table 3. Multivariate analysis
Characteristics
Mutational status
BRAF V600E mut
BRAF rare mut
ECOG PS
0
1–2
Primary tumor site
Left colon/rectum
Right colon
Time to metastases
Metachronous
Synchronous
No. of metastases sites
1
>1
N
Overall survival
HR
95% CI
P
77
10
1
0.21
–
0.07–0.64
–
0.006
52
24
1
1.91
–
1.06–3.45
–
0.033
37
50
1
1.33
–
0.69–2.56
–
0.398
26
61
1
0.72
–
0.35–1.47
–
0.363
39
48
1
1.74
–
0.99–3.04
0.054
Bold values indicate significance level set at 0.05.
Six (60%) of 10 patients bearing BRAF 594 or 596 mutated
tumors underwent radical resections of their metastases, when
compared with 9 (12%) of 77 patients BRAF V600E mutation
(P = 0.001). When including the radical resection of metastases
as a covariate in the multivariable model, BRAF 594 or 596
mutations retained their positive association with OS [HR: 0.27
(95% CI 0.08–0.86), P = 0.027] (supplementary Table S1, available at Annals of Oncology online).
discussion
BRAF codons 594 and 596 mutations identify mCRCs with different clinical, pathological and prognostic features when compared with BRAF V600E mutated tumors. Notably, while the
frequency of MSI high in BRAF V600E mutated tumors is relatively high even in the metastatic stage (∼20%), all BRAF codons
594 or 596 mutated samples were classified as microsatellite
stable. Moreover, while the concomitant detection of RAS and
BRAF V600E mutations is extremely rare (0–0.001%), since they
are mutually exclusive drivers of oncogene addiction, our nextgeneration sequencing results show the concomitant presence of
RAS and BRAF codons 594 or 596 mutations in 2 of 10 samples.
Notably, the HS for these mutations is significantly lower in
samples bearing other molecular alterations activating the EGFR
pathway than in samples not bearing other alterations. This suggests that, at least in some cases, rare BRAF mutations may confer
less proliferative advantage to cancer cells when compared with
other mutations with a negative prognostic impact.
Overall, these results lead to conclude that the clinical and
biological impact of BRAF codons 594 and 596 mutations is
profoundly different than BRAF V600E. Even if some clinical
differences between BRAF codons 594 or 596 mutated and wildtype tumors were described, and a trend toward longer survival
was observed, further investigations are needed to confirm the
peculiarity of these rare molecular alterations among non-V600E
mutated tumors.
Table 4. Systemic and locoregional treatments delivered to patients with BRAF 594 or 596 mutated tumors
Patient
ID
First-line treatment
Second-line treatment
Third-line treatment
Notes
1-1
1-2
FOLFOXIRI + cetuximab → R0 liver resection
R0 hepatectomy → capecitabine
FOLFIRI + cetuximab
XELOX
FOLFOX
Capecitabine
1-3
NA
NA
1-4
FOLFOXIRI + bevacizumab → R0 pelvic
resection
FOLFOXIRI + bevacizumab
–
Contraindication to intensive
chemotherapy (frail elderly)
–
NA
NA
2-5
XELOX → R0 lung resection
R0 lung metastasectomy
NA
2-6
XELOX + bevacizumab
CAPIRI + cetuximab
2-7
2-8
Capecitabine, oxaliplatin,
irinotecan + cetuximab (COI-E) → R0 liver
resection
FOLFIRI + cetuximab
XELOX → stereotactic radiotherapy
Temozolomide
NA
3-9
3-10
FOLFIRI + cetuximab → R0 liver resection
FOLFIRI
5-FU/LV + bevacizumab
Capecitabine → stereotactic
radiotherapy
5-FU/LV
FOLFOX
Volume 26 | No. 10 | October 2015
NA
5-FU/LV
Complete response after
FOLFOXIRI + bevacizumab
Not evident disease after R0 lung
resection (DFS: 60 months)
–
Prior adjuvant FOLFOX
Contraindication to intensive
chemotherapy (frail elderly)
Prior adjuvant FOLFOX
–
doi:10.1093/annonc/mdv290 | 
original articles
Clear limitations of our analysis are the low number of BRAF
594 and 596 mutated patients, in line with the very low frequency
of these alterations, and the retrospective nature of the present
series.
We could not assess the efficacy of anti-EGFR monoclonal
antibodies in this rare population, since none of BRAF 594 or
596 mutated patients received an anti-EGFR as monotherapy.
However, De Roock et al. reported in the wide series of the
European Consortium (N = 773) that a patient bearing BRAF
D594G mutated mCRC achieved response to cetuximab monotherapy [21]. Based on these findings, BRAF 594 or 596 mutated
patients should not be excluded from receiving anti-EGFR
monoclonal antibodies.
At the same time, the absence of a negative prognostic impact
may have important implications in the daily management of
these patients, also with regard to the choice of the intensity of
the first-line chemotherapy regimen.
Is there a biological rationale supporting present findings? It
is well known that BRAF V600E protein is 500-fold activated and
stimulates constitutive MEK–ERK signaling in cells. Preclinical
data show that BRAF 594 and 596 mutations are not responsible
for the hyperactivation of the downstream kinase pathways [22].
In fact, even if codons 594 and 596 are located in the kinase
activation segment of BRAF, they are DFG motif inactivating
mutations, associated with impaired transforming ability [23].
Conformational changes induced by BRAF 594 and 596 mutations increase the heterodimerization of BRAF with wild-type
CRAF [24], thus inducing an indirect and modest activation of
MAPK pathway [25]. This is in line with preclinical data on a
BRAF G596R mutated cell line (NCIH508) showing sensitiveness to anti-EGFR treatment [26].
In conclusion, BRAF 594 or 596 mutations identify a rare
and previously unexplored molecular subtype of mCRC with
clinical and pathological features different from BRAF V600E
mutated. This novel knowledge provides an intriguing background to investigate new target approaches in this patients’
population and represents a progress toward more personalized
cancer medicine.
acknowledgements
Molecular analyses at Azienda Ospedaliera-Universitaria Pisana
were supported by ARCO Foundation. Molecular analyses at
Fondazione IRCCS Istituto Nazionale dei Tumori were supported by institutional funds. Investigators at Niguarda Cancer
Center (AA, ASB, CL, SS) are supported by grants Terapia
Molecolare dei Tumori from Fondazione Oncologia Niguarda
Ca’ Granda Onlus (ASB, SS), Special Project Clinical Molecular
Oncology AIRC 5x1000 (SS), and EC 7th Framework Colon
Therapy Research COLTHERES grant (SS).
funding
Supported by ARCO Foundation and Fondazione IRCCS
Istituto Nazionale dei Tumori’s institutional funds, grants
Terapia Molecolare dei Tumori from Fondazione Oncologia
Niguarda Ca’ Granda Onlus, Special Project Clinical Molecular
Oncology AIRC 5x1000 and EC 7th Framework Colon Therapy
Research COLTHERES grant.
 | Cremolini et al.
Annals of Oncology
disclosure
The authors have declared no conflicts of interest.
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Annals of Oncology 26: 2097–2101, 2015
doi:10.1093/annonc/mdv316
Published online 27 July 2015
Comparison of two different S-1 plus cisplatin dosing
schedules as first-line chemotherapy for metastatic
and/or recurrent gastric cancer: a multicenter,
randomized phase III trial (SOS)
M.-H. Ryu1, E. Baba2, K. H. Lee3, Y. I. Park4, N. Boku5, I. Hyodo6, B.-H. Nam7, T. Esaki8, C. Yoo1,
B.-Y. Ryoo1, E.-K. Song9, S.-H. Cho10, W. K. Kang11, S. H. Yang12, D. Y. Zang13, D. B. Shin14,
S. R. Park1, K. Shinozaki15, T. Takano16 & Y.-K. Kang1* on behalf of the SOS study investigators
1
Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; 2Department of Comprehensive Clinical Oncology,
Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan; 3Department of Hemato-oncology, Yeungnam University Hospital, Daegu; 4Center for Gastric
Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Gyeonggi, Korea; 5Department of Clinical Oncology, St Marianna University School of
Medicine, Kawasaki; 6Division of Gastroenterology, University of Tsukuba, Tsukuba, Japan; 7Biometric Research Branch, National Cancer Center, Goyang,
Gyeonggi, Korea; 8Department of Gastrointestinal and Medical Oncology, National Kyushu Cancer Center, Fukuoka, Japan; 9Division of Hematology/Oncology,
Department of Internal Medicine, Chonbuk National University Medical School, Jeonju; 10Department of Hematology-Oncology, Chonnam National University
Hwasun Hospital, Gwangju; 11Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School Medicine,
Seoul; 12Department of Internal Medicine, Korea Cancer Center Hospital, Seoul; 13Division of Hematology-Oncology, Department of Internal Medicine, Hallym
University Medical Center, Hallym University College of Medicine, Anyang; 14Division of Hematology/Oncology, Department of Internal Medicine, Gachon University
Gil Hospital, Incheon, Korea; 15Division of Clinical Oncology, Hiroshima Prefectural Hospital, Hiroshima; 16Department of Medical Oncology, Toranomon Hospital,
Minato-ku, Japan
Received 17 April 2015; revised 17 July 2015; accepted 20 July 2015
Background: Five-weekly S-1 plus cisplatin (SP5) is one of the standard first-line regimens for advanced gastric cancer
(GC), proven in a Japanese phase III study. To enhance the dose intensity of cisplatin, 3-weekly S-1 plus cisplatin (SP3)
was developed.
Patients and methods: This multicenter, randomized, open-label, phase III study evaluated whether SP3 (S-1 80 mg/
m2/day on days 1–14 and cisplatin 60 mg/m2 on day 1) was noninferior/superior to SP5 (S-1 80–120 mg/day on days
1–21 and cisplatin 60 mg/m2 on day 1 or 8) in terms of progression-free survival (PFS). Chemotherapy-naive patients with
metastatic, recurrent gastric or gastroesophageal junction adenocarcinoma were randomized 1 : 1 to receive either SP3
or SP5. The trial is registered at ClinicalTrials.gov (NCT00915382).
Results: Between February 2009 and January 2012, 625 patients were randomized at 42 sites in Korea and Japan.
With a median follow-up duration of 32.4 months (range, 13.3–48.6 months) in surviving patients, SP3 was not only noninferior but also superior to SP5 in terms of PFS [median 5.5 versus 4.9 months; hazard ratio (HR) = 0.82; 95% confidence interval (CI) 0.68–0.99; P = 0.0418 for superiority). There was no difference in overall survival (OS) between the
*Correspondence to: Prof. Yoon-Koo Kang, Department of Oncology, Asan Medical
Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul
138–736, Korea. Tel: +82-2-3010-3230; Fax: +82-2-3010-8772; E-mail: ykkang@amc.
seoul.kr
© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: [email protected].