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Annals of Oncology
and PFS (aHR 2.3 [95% CI: 1.6-3.1; p = 8x10E-7]), compared to the wildtypes.
Similar findings were observed for the BRM-1321 homozygous variants (aHR for OS
of 2.5 [95% CI: 1.7-3.5; p = 1.1x10E-6]; aHR for PFS of 1.9 [95% CI: 1.3-2.6;
p = .0004]). Finally, the presence of double homozygous BRM-741 and BRM-1321
variants was strongly associated with substantially worse OS (aHR 4.4 [95% CI:
2.7-7.1, p = 1x10E-9]) and PFS (aHR 3.6 [95% CI: 2.3-5.6, p = 2x10E-8]).
Conclusion: The same two homozygous BRM promoter variants that are associated
with increased risk of lung cancer are also strongly associated with adverse OS and
PFS in this cohort of stage IV NSCLC patients. Validation of the results in
prospective clinical trials is underway and will better elucidate whether these BRM
promoter variants are prognostic or predictive.
Disclosure: All authors have declared no conflicts of interest.
187P RIBONUCLEOTIDE REDUCTASE SUBUNIT 2 (RRM2)
PREDICTS SHORTER SURVIVAL IN RESECTED STAGE I-III
NON-SMALL CELL LUNG CANCER (NSCLC) PATIENTS
F. Grossi 1 , G. Barletta 1 , C. Sini 1 , E. Rijavec 1 , C. Genova 1 , M.G. Dal Bello 1 ,
G. Savarino 2 , M. Truini 3 , F. Merlo 2 , P. Pronzato 4
1 Lung Cancer Unit, National Institute for Cancer Research, Genoa, ITALY,
2 Epidemiology, National Institute for Cancer Research, Genoa, ITALY,
3 Department of Pathology, IRCCS AOU San Martino-IST, Genoa, ITALY,
4 Oncologia Medica A, IRCCS AOU San Martino - IST-Istituto Nazionale per la
Ricerca sul Cancro, Genova, ITALY
Background: Biomarkers can help in identifying patients (pts) with early-stage
NSCLC with high risk of relapse and poor prognosis. The aim of this study was to
investigate the relationship between the levels of expression of 7 biomarkers, various
clinicopathological characteristics and their prognostic significance.
Methods: Tumor tissue from 82 radically resected stage I-III NSCLC pts were
consecutively collected to investigate the mRNA expression and protein levels of the
following biomarkers using quantitative reverse transcriptase real-time PCR
(qRT-PCR) and immunohistochemistry (IHC) with a tissue microarray technique:
excision repair cross-complementation group 1 (ERCC1), breast cancer 1 (BRCA1),
ribonucleotide reductase subunit 1 (RRM1), RRM2, p53R2, thymidylate synthase
(TS) and class III beta-tubulin (β-Tub-III).
Results: On a univariate analysis, p53R2 expression was significantly higher in
adenocarcinoma (ADK) compared to squamous cell carcinoma (SSC) samples (p =
0.002) and in stage I compared to stage II-III (p ≤ 0.001). ERCC1 expression was
significantly higher in females compared to males (p = 0.03), and β-Tub-III
expression was significantly higher in ADK than in SSC (p = 0.03). Pts with lower
RRM2 expression survived longer than pts with higher RRM2 expression (p = 0.069).
The multivariate analysis confirmed RRM2 as an independent prognostic marker of
shorter survival (p= 0.031). The comparison between survival curves with qRT-PCR
and IHC showed similar results with a trend towards longer survival among ERCC1
negative pts, BRCA1 negative pts, p53R2 positive pts and among pts with low levels
of RRM1 and RRM2, although the difference was not statistically significant with
both methods. qRT-PCR and IHC have shown that β-Tub-III and TS had no
significant impact on survival.
Conclusions: This is the first study that identifies RRM2 expression as a negative
prognostic factor in resected stage I-III NSCLC. Moreover, we have demonstrated the
differential expression of p53R2 and β-Tub-III in ADK compared to SSC and higher
expression of p53R2 in pts with stage I compared to stage II-III NSCLC.
Disclosure: All authors have declared no conflicts of interest.
188P TROPOMYOSIN-RELATED KINASE B IS A THERAPEUTIC
TARGET AND PROGNOSTIC FACTOR FOR AGGRESSIVE LUNG
CANCER INCLUDING LCNEC
S. Odate 1 , K. Nakamura 2 , H. Onishi 1 , A. Uchiyama 3 ,M.Kato 4 , M. Tanaka 2 ,
M. Katano 1
1 Cancer Therapy and Research, Kyushu University, Fukuoka, JAPAN, 2 Surgery
and Oncology, Kyushu University, Fukuoka, JAPAN, 3 Surgery, Kyushu Kosei
Nenkin Hospital, Fukuoka, JAPAN, 4 Surgery, Hamanomachi Hospital, Fukuoka,
JAPAN
Background: Lung cancer is one of the most common types of cancer, accounting
for more deaths than any other types of cancer. Tropomyosin-related kinase B
(TrkB) has previously been shown to be important in tumor progression in
neuroblastoma, pancreatic cancer, and prostate cancer. However, little is known
about biological significance of TrkB in human lung cancer. Here we investigate if
TrkB may be a therapeutic target and prognostic factor for lung cancer.
Methods: Surgically resected specimen; The expression of TrkB and its ligand BDNF
(Brain-derived neurotrophic factor) were investigated in 104 patients with primary
lung cancers (8 small cell carcinomas, 11 large cell neuroendocrine carcinomas, 10
large cell carcinomas, 20 adenocarcinomas, 55 squamous cell carcinomas) by
immunohistochemical staining. In vitro assay; Large cell neuroendocrine carcinoma
(LCNEC) cell lines (NCI-H460 and NCI-H810) expressing TrkB were used.
TrkB-siRNA and TrkB tyrosine kinase inhibitor (K252a) were used to inhibit TrkB.
BDNF-siRNA was used to inhibit BDNF. Cell proliferation and invasion were
evaluated by MTT and Transwell assays, respectively.
Results: 1) There were significantly higher TrkB and BDNF expressions in LCNEC
cases than any other histological types. LCNEC cases also had poorer prognosis than
any other histological types. 2) Higher expression of TrkB positively correlated with
disease free survival (p < 0.001) and overall survival (p < 0.05) in all histological types.
3) BDNF upregulated the invasion of LCNEC cell lines. 4) Knockdown of TrkB or
BDNF mRNA expression using siRNA significantly decreased the invasion of LCNEC
cell lines. K252a also significantly decreased the invasion of LCNEC cell lines.
Conclusions: These data suggests that BDNF/TrkB signal is important in LCNEC
and TrkB is a potential therapeutic target and prognostic factor for aggressive lung
cancer including LCNEC.
Disclosure: All authors have declared no conflicts of interest.
189P REDUCED CYP2D6 FUNCTION POTENTIATES THE
GEFITINIB-INDUCED RASH IN PATIENTS WITH NON-SMALL
CELL LUNG CANCER
T. Suzumura 1 , T. Kimura 1 , S. Kudoh 1 , K. Umekawa 1 , M. Nagata 1 , Y. Kira 2 ,
T. Nakai 1 , K. Matsuura 1 , N. Yoshimura 1 , K. Hirata 1
1 Respiratory Medicine, Osaka City University, Osaka, JAPAN, 2 Department of
Central Laboratory, Osaka City University, Osaka, JAPAN
Background: Rash, liver dysfunction, and diarrhea are known as adverse events of
erlotinib and gefitinib. However, clinical trials with gefitinib have reported different
proportion of adverse events compared to those with erlotinib. In an in vitro study,
cytochrome P450 (CYP) 2D6 was shown to be involved in the metabolism of gefitinib
and not of erlotinib. It has been hypothesized that CYP2D6 phenotypes may be
implicated in different adverse events between in the gefitinib and erlotinib therapies.
Methods: The frequency of each adverse event was evaluated during the period that
the patients received EGFR-TKI therapy. CYP2D6 phenotypes were determined from
the CYP2D6 genotype using real-time polymerase chain reaction methods, which are
able to determine single nucleotide polymorphisms. The CYP2D6 phenotypes were
categorized into 2 groups according to functional or reduced metabolic levels. In
addition, we evaluated the odds ratio (OR) of adverse events with each factor,
including CYP2D6 activities as well as treatment types.
Results: Patients were identified through a query of patient information for subjects
prospectively enrolled in the Medical Information System within Osaka City
University Hospital between January 1999 and February 2012 that tracks all of the
patients referred for CYP2D6 sequencing from our hospital. A total of 232 patients
received gefitinib therapy, and 86 patients received erlotinib therapy. Reduced
function of CYP2D6 was associated with an increased risk of rash of grade 2 or more
(OR 0.44, 95% confidence interval [CI] 0.21-0.94, p = 0.03), and not of diarrhea ≥
grade 2 (OR 0.49, 95%CI 0.17-1.51, p = 0.20) and liver dysfunction ≥ grade 2 (OR
1.08, 95%CI 0.52-2.34, p = 0.84) in gefitinib cohort. No associations were observed
between any adverse events in erlotinib cohorts and CYP2D6 phenotypes (rash: OR
1.77, 95%CI 0.54-6.41, p = 0.35; diarrhea: OR 1.08, 95%CI 0.21-7.43, p = 0.93; and
liver dysfunction: OR 0.93, 95%CI 0.20-5.07, p = 0.93).
Conclusions: CYP2D6 may relate to the metabolism of gefitinib and not of erlotinib.
CYP2D6 phenotypes are one of promising factors for the development of rash in
gefitinib therapy.
Disclosure: All authors have declared no conflicts of interest.
190P INCREASE OF PLASMA ADIPONECTIN LEVELS AND
DECREASE OF PRO-INFLAMMATORY CYTOKINES IN
NON-SMALL CELL LUNG CANCER PATIENTS TREATED
WITH EGFR-TKIS
K. Umekawa 1 , T. Kimura 1 , T. Suzumura 2 , S. Kudoh 1 , T. Nakai 1 , M. Nagata 1 ,
K. Matsuura 1 , S. Mitsuoka 1 , N. Yoshimura 1 , K. Hirata 1
1 Respiratory Medicine, Osaka City University, Osaka, JAPAN, 2 Department of
Respiratory Medicine, Graduate School of Medicine, Osaka City University,
Osaka, JAPAN
Background: Malnutrition in non-small cell lung cancer (NSCLC) is associated with
advanced stage of disease and is needed for careful choice of treatment. The
epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are
routinely used for the treatment of advanced NSCLC with EGFR active mutations,
which are promising the excellent responses. Recently, pro-inflammatory cytokines
have been proposed as mediators of cancer cachexia. Adipose tissue produces and
release substances called adipokines which include tumor necrosis factor-alpha
(TNF-α), leptin, adiponectin, and resistin. Adiponectin suppresses the secretion of
inflammatory cytokines such as IL-8, TNF-α, and induces the secretion of
anti-inflammatory cytokines such as IL-10. It has been hypothesized that EFGR-TKI
therapy may affect this adipokine network.
Methods: The prospective study which evaluated correlations between the pre and
post-treatment point of days 30 plasma adipokines and cytokines after EGFR-TKIs
administration and clinical outcomes in advanced NSCLC was conducted at Osaka
City University Hospital. Plasma adipokines and cytokines were analyzed by
Luminex 200 PONENT system (Milliplex MAP kits; Millipore).
Results: A total of 33 patients were enrolled. We obtained plasma samples for
analyses 33 patients on pre-treatment point, and 23 patients on days 30 point.
Volume 23 | Supplement 9 | September 2012 doi:10.1093/annonc/mds391 | ix79