Annals of Oncology

abstracts
Annals of Oncology
Conclusions: This study provides evidence that functional germline polymorphisms in
the VEGF pathway may be helpful as prognostic biomarkers in colon cancer.
Legal entity responsible for the study: Hospital de la Santa Creu i Sant Pau (Barcelona)
Funding: Hospital de la Santa Creu i Sant Pau (Barcelona)
Disclosure: All authors have declared no conflicts of interest.
99P
Clinical characteristics in colorectal cancer harboring BRAF
V600E and non-V600E mutations
E. Shinozaki 1 , Y. Miki 2 , M. Ueno 3 , M. Igarashi 4 , K. Chin 1 , D. Takahari 1 , M. Ogura 1 ,
T. Ichimura 1 , I. Nakayama 1 , H. Osumi 1 , T. Wakatsuki 1 , T. Matsushima 1 ,
K. Yamaguchi 1
1 Department of GI Oncology, Cancer Institute Hospital of JFCR, Tokyo, Japan,
2 Lab of Genetic Diagnosis, Cancer Institute Hospital of JFCR, Tokyo, Japan,
3 Department of Gastroenterological Surgery, Cancer Institute Hospital of JFCR,
Tokyo, Japan, 4 Department of Gastroenterology, Cancer Institute Hospital of
JFCR, Tokyo, Japan
Background: BRAF V600E mutation (MT) in metastatic colorectal cancer (CRC) has
been known thoroughly as a prognostic biomarker, and as a negative predictive
biomarker for anti-EGFR treatment. On the other hand, the feature of BRAF MTs
other than BRAF V600E still remains unclear. This study aimed to reveal the clinical
characteristics of BRAF non-V600E MTs compared with the EGFR signaling pathway
MTs status including BRAF V600E MT.
Methods: Consecutive patients from June 2012 to November 2013 were enrolled in this
study. Multiplex genotyping of EGFR signaling pathway was performed on archival
samples using Luminex Assay (MABGEN, GENOSEARCH Mu-PACK and
GENOSEARCH BRAF, MBL) for BRAF V600E / BRAF non-V600E , KRAS including exon
2, 3 and 4, NRAS, and PIK3CA. We analyzed the correlation among MTs profile,
clinical data and location of CRC.
Results: A total of 824 CRC patients was analyzed; consisted of 374 females and 450
males, 147, 200, 263 and 214 in stage I, II, III and IV or recurrent CRC, respectively.
The incidence of MTs were as followings; BRAF V600E / BRAF non-V600E , KRAS
including exon 2, 3 and 4, NRAS and PIK3CA were 5.3% / 1.7%, 41.5%, 3.3% and
9.7%, respectively. The relationship among main characteristics and mutational status
showed in table below. Although RAS and BRAF V600E MTs were in a mutually
exclusive manner, one case of co-mutation with KRAS A146T MT was observed in
BRAF non-V600E cases. In both BRAF V600E MT and BRAF non-V600E MT, four cases were
having co-mutation with PIK3CA MTs.
female/
male
n = 374/
450
Table: 99P
right/ left +rectum*
n = 235/ 589
(335 + 254)
por/
others**
n = 47/
777
stage I/ II/ III/
IV + rec***
n = 147/ 200/
263/ 214
BRAF V600E n = 44 24/ 20 33/ 11 (8 + 3) 9/ 35 7/ 11/ 9/ 17
BRAF non-V600E n = 14 7/ 7 3/ 11 (4 + 7) 1/ 13 4/ 4/ 3/ 3
KRAS exon2 n = 307 153/ 154 116/191(89 + 102) 9/ 298 52/ 76/ 102/ 65
KRAS exon3,4 n = 35 17/ 18 4/ 31 (16 + 15) 2/ 33 6/ 6/ 17/ 5
NRAS n = 27 13/ 14 2/ 25 (11 + 14) 0/ 27 2/ 7/ 8/ 9
PIK3CA n = 80 32/ 48 38/ 42 (17 + 25) 2/ 78 15/ 25/ 23/ 17
Abbreviation; *right/ left-sided colon; ** poorly differentiate; *** recurrence
Conclusions: In this analysis BRAF non-V600E MTs were identified as a rare fraction and
had no specific character revealed in contrast to the BRAF V600E MT, which was more
frequent in right-sided primary, female and poorly differentiated histology. Further
more large-scale investigation in this rare fraction of BRAF non-V600E MTs will be
necessary to clarify its clinical meaning for precision medicine.
Legal entity responsible for the study: N/A.
Funding: Japanese Foundation for Cancer Research
Disclosure: All authors have declared no conflicts of interest.
100P
5-fluorouracil degradation rate as a predictive toxicity
biomarker in early stage gastrointestinal cancer
M. Roberto 1 , A. Romiti 1 , A. Botticelli 2 , F.R. Di Pietro 1 , L. Lionetto 3 , G. Gentile 3 ,
F. Mazzuca 1 , R. Falcone 1 , M. Occhipinti 1 , S. Macrini 1 , E. Anselmi 1 , A. Petremolo 1 ,
C.E. Onesti 1 , M. Simmaco 3 , P. Marchetti 1
1 Clinical and Molecular Medicine, Azienda Ospedaliera St. Andrea - Roma, Rome,
Italy, 2 Medical Oncology, Azienda Ospedaliera St. Andrea - Roma, Rome, Italy,
3 NESMOS, Sapienza University, Rome, Italy
Background: Prediction and early management of severe toxicity might avoid both
therapy’s interruption and the benefit loss of adjuvant chemotherapy. However,
predictive toxicity biomarkers are not yet available. The aim of this study was to
investigate whether polymorphisms of different genes involved in fluoropyrimidine
metabolism and 5-fluorouracil (5-FU) degradation rate were associated with clinical
outcome of oral fluoropyrimidine-based adjuvant chemotherapy in patients with early
stage GI cancer.
Methods: Genotyping of DPYD IVS14 IVS 14 + 1 G > A, MTHFR C677T and A1298C
SNPs were performed by pyro-sequencing technology. PCR analysis was used for
genotyping TYMS-TSER. Using PBMC cells, we also evaluated the 5-FU degradation
rate, which determines the amount of drug consumed by cells in a time unit. Patients
were categorized in two groups according to their value of 5-FU degradation rate:
below the 5th centile (poor metabolism - PM) or above the 95th centile (ultra-rapid
metabolism - UM) and within 5-95th centile (0.85-2.2 ng/ml/10 6 cells/min).
Results: One hundred forty-two patients with early stage colon (39%), rectal (28%),
stomach (20%) and pancreatic (13%) cancer, treated with 5FU-based adjuvant
monochemotherapy, were included in this retrospective analysis. Forty-three per cent of
patients had a lymphnode-positive disease, and 37% received concomitant radiotherapy.
Most of patients had an ECOG PS = 0-1. Seventy-four and 20% of the patients suffered
from at least one G1-4 and G3-4 adverse events (12 hematologic, 24 GI, 12 HFS),
respectively. Sixteen (11%) patients resulted abnormal 5-FU metabolizers. At a
multivariate logistic regression analysis, an altered 5-FU degradation rate (2.10)
resulted significantly associated with both G1-4 hematologic (OR = 2.99, 95% CI 0.98-9.12,
P = 0.05) and all grade 3-4 adverse events (OR = 4.39, 95% CI 1.40-13.80, P = 0.01). No
correlation was reported between toxicity and each tested gene polymorphism.
Conclusions: Our study showed a statistically significant association between 5-FU
degradation rate and both G1-4 hematologic and all G3-4 toxicities. Therefore, the
5FU-degradation rate may be considered as a putative, predictive biomarker of
fluoropyrimidine-related toxicity.
Legal entity responsible for the study: N/A
Funding: Self-funded
Disclosure: All authors have declared no conflicts of interest.
101P
Predictive value of vascular endothelial growth factor A
(VEGF-A) for bevacizumab-based treatments across advanced
cancers: a meta-analysis based on eight phase III randomized
control trials involving 4,523 patients
S. Tang, Y. Zhang, W. Liang, J. He
Department of Thoracic Oncology, The 1st Affiliated Hospital of Guangzhou
Medical University, Guangzhou, China
Background: Bevacizumab, a monoclonal antibody against vascular endothelial growth
factor (VEGF), has been shown to be beneficial for patients with advanced cancer in
phase III randomized control trials which had associated biomarker analyses. We aim
to evaluate the predictive value of circulating VEGF-A on patient survival in these
studies.
Methods: PubMed was searched for eligible trials from the date of inception to 31st
December, 2015. Based on the median circulating level of VEGF-A in each trial, we
conducted a meta-analysis with random-effect model to estimate the treatment effects
between bevacizumab-based treatments and treatments without bevacizumab on
progression-free survival (PFS) and overall survival (OS). Interaction test was used to
examine the predictive value.
Results: Eight studies were included, involving 4,523 patients analyzed with VEGF-A
level. Patients following bevacizumab-based treatments had significantly prolonged
PFS regardless of VEGF-A level (high:HR = 0.70 [95 % CI 0.63-0.77], P < 0.001, I2=
0%; low: HR = 0.78 [0.70-0.87], P < 0.001, I2= 3%). No significant interaction effect was
observed (Chi 2 = 5.15, P = 0.12). Although significant benefit on OS was exclusively
shown in patients with higher VEGF-A level (high: HR = 0.83 [0.73-0.95], P = 0.005,
I2= 0%; low: HR = 0.96 [0.83-1.10], P = 0.55, I2= 4%) but there was still no interaction
effect between stratified groups (Chi 2 = 5.15, P = 0.14). Subgroup analysis revealed
potential VEGF-A subgroup differences in patients with breast cancer and gastric
cancer but not lung cancer and colorectal cancer. However, tumor type was not a
source of heterogeneity during synthesis on PFS or OS.
Conclusions: There is still insufficient evidence to support the use of VEGF-A as a
predictive biomarker for bevacizumab-based treatment in advanced cancers.
Legal entity responsible for the study: N/A
Funding: The First Affiliated Hospital of Guangzhou Medical University
Disclosure: All authors have declared no conflicts of interest.
102P
Large scale DFNA5 methylation and expression analysis in
primary breast adenocarcinoma using data from the Cancer
Genome Atlas
L. Croes 1 , M. Beyens 1 , E. Franssen 2 , A. Goepfert 1 , M. Peeters 3 , P. Pauwels 4 ,
G. Van Camp 2 , K. Op De Beeck 1
1 Oncology - Medical Genetics, University of Antwerp-Campus Drie Eiken,
Antwerp, Belgium, 2 Medical Genetics, University of Antwerp-Campus Drie Eiken,
Antwerp, Belgium, 3 Department of Oncology, University Hospital Antwerp,
Edegem, Belgium, 4 Department of Molecular Pathology, University Hospital
Antwerp, Edegem, Belgium
Background: Methylation of promotor CpG islands is frequently associated with
transcriptional silencing and may serve as a mechanism to inactivate tumor suppressor
vi30 | abstracts Volume 27 | Supplement 6 | 2016