Annual Meeting Proceedings Part 1 - American Society of Clinical ...

10610 General Poster Session (Board #51C), Mon, 1:15 PM-5:15 PM
Cytokeratin 19 fragment (CYFRA21-1) to predict the efficacy of epidermal
growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) in non-small
cell lung cancer (NSCLC) harboring EGFR mutation. Presenting Author:
Kosuke Tanaka, Division of Integrated Oncology, Institute of Biomedical
Research and Innovation, Kobe, Japan
Background: EGFR mutation is independently associated with a favorable
response in NSCLC patients receiving EGFR-TKIs, regardless of gender or
smoking history. However, recent reports have indicated that squamous
cell carcinoma patients harboring EGFR mutations show a worse response
to EGFR-TKIs than adenocarcinoma patients. We hypothesized that serum
CYFRA21-1 is a predictive marker in EGFR mutated patients treated with
EGFR-TKIs. Methods: We retrospectively screened 160 NSCLC patients
harboring EGFR mutations (exon 19 deletions, L858R in exon 21, or other
minor mutations) who received either gefitinib or erlotinib between 1992
and 2011. Patients were screened for histology, sex, age, smoking status,
efficacy of EGFR-TKI and tumor markers (CEA/CYFRA21-1) at initial
diagnosis. Results: Out of 160 eligible patients treated with EGFR-TKIs, 77
patients with high CYFRA21-1 level (�2 ng/ml) showed statistically shorter
progression-free survival (PFS) than 83 patients with normal CYFRA21-1
level (median PFS 7.5 vs 14.0 months, p�0.006). No significant difference
in PFS was observed between high CEA group (�5 ng/ml) and normal
CEA group (median PFS 8.6 vs 11.2 months, p�0.2423). Multivariate
analysis revealed that high CYFRA21-1 level is independently associated
with PFS (HR 1.35; p�0.002) as well as squamous cell carcinoma (HR
1.40; p�0.020) and performance status 2-4 (HR 2.63; p�0.003). No
statistically significant difference in overall survival (OS) was observed
between high CYFRA21-1 group and normal group (median OS 24.8 vs
39.1 months, p�0.104). Conclusions: High CYFRA level patients have
significantly shorter PFS, which may indicate that this subgroup has a
larger squamous component and thus less response to EGFR-TKIs. Serum
CYFRA21-1 level is a predictive marker of EGFR-TKIs efficacy and EGFR
mutated patients can be divided into two subgroups according to CY-
FRA21-1 level at initial diagnosis.
10612 General Poster Session (Board #51E), Mon, 1:15 PM-5:15 PM
Use of proteomic analysis of LKB1/AMPK/mTOR pathways to identify
IGF-1R pathway upregulation with LKB1 loss or mTOR inhibition in
NSCLC: Implications for targeted combinations. Presenting Author: Emrullah
Yilmaz, Baylor College of Medicine, Houston, TX
Background: LKB1 is a serine/threonine kinase which is mutated in
20-30% of non-small cell lung cancers (NSCLC) and functions as a tumor
suppressor by activating AMPK. Loss of LKB1 by point mutation or deletion
suppresses AMPK, leading to increased mTOR signaling. We investigated
the signaling pathways modulated by LKB1 mutations and by mTOR
inhibition in NSCLC. Methods: Protein expression in cell lines was measured
by reverse phase protein array. Differences in protein expression at
baseline in LKB1 wild-type versus mutant cell lines and the effects of
protein modulation by treatment were assessed by ANOVA. Results: LKB1
mutant cell lines had lower expression of phosphorylated AMPK and TSC
(p�0.01 for both) consistent with prior observations. In addition, mutant
cell lines expressed higher levels of proteins in the IGF1R pathway
including IGFR1b (p�0.0001); AIB1, which is known to upregulate IGF1
(p�0.0001); and IGFBP2 (p�0.016). LKB1 mutant cell lines (n�11/25)
were 1.5-fold more sensitive to the AMPK activator metformin, although
this did not reach statistical significance (p�0.10). Expression levels of
IGF1R pathway proteins increased significantly after 48h treatment with
metformin, the mTOR inhibitor temsirolimus, and the dual PI3K/mTOR
inhibitor PI103. For example, IGFBP2 and AIB1 were elevated after
metformin treatment (p�0.02 and 0.005, respectively); IRS1 and IGFR1
were elevated after temsirolimus or PI103 (p�0.05 for both). Following
treatment with metformin and temsirolimus, there was also increased pAkt,
a downstream target of IGF1R and activator of mTOR (p�0.01 for both).
Modulation of the IGF1R pathway by these drugs was independent of LKB1
mutation status. Conclusions: LKB1 mutant cell lines have increased IGFR
activity with higher baseline IGFR1, IGFB2 and AIB1, suggesting that IGFR
may be a potential therapeutic target in LKB1 mutant tumors. In addition,
inhibition of the mTOR pathway upregulates the IGFR pathway possibly as
a feedback mechanism. These results support the investigation of IGFR
inhibitors in combination with drugs targeting the mTOR pathway, particularly
for tumors bearing LKB1 mutations.
Tumor Biology
683s
10611 General Poster Session (Board #51D), Mon, 1:15 PM-5:15 PM
Evaluation of EZH2 SNPs in cholangiocarcinoma patients. Presenting
Author: Elisa Paolicchi, Department of Internal Medicine, University of
Pisa, Pisa, Italy
Background: Cholangiocarcinoma (CCA) is an aggressive tumor arising from
biliary tract epithelium.CCA is the second most common primary hepatic
malignancy, with a progressive increasing incidence in western countries.
Polycomb group protein Enhancer of Zeste homolog 2 (EZH2) is overexpressed
in several human carcinomas, including CCA, where EZH2 overexpression
is associated with tumor progression. The aim of this study is to
evaluate the correlation between candidate EZH2 Single Nucleotide
Polymorphisms (SNPs) with clinical outcome in CCA patients. Methods:
Genomic DNA was extracted from blood samples of 75 patients [44 male
and 31 female, with average age of 62.3 (range, 26-80 years)] affected by
hystologically confirmed advanced CCA, treated with the epirubicincisplatin-xeloda
(ECX) regimen. We performed an in silico characterization
to select EZH2 SNPs (rs2302427 C/G, rs6464926 C/T, rs17171119 T/G
and rs887569 C/T) from 26 EZH2 SNPs described previously. Genotyping
was performed through Taqman PCR. Prognostic value of selected EZH2
SNPs was assesses by correlation with time to progression (TTP) and overall
survival (OS). OS and TTP curves were obtained through Kaplan-Meier
method, and comparison with survival distribution was evaluated with
logrank test. Results: Through specific software (PROMO 3.0, MicroSNiper
and Gene Card) we performed an in silico analysis based on functional
characterization criteria (transcription factor binding-TFB, miRNA binding
and missense mutations). We selected 4 EZH2 SNP alleles showing
specific relevance in CCA because of their differential TFB affinity
(PPAR�/RXR�, E2F-1, Pax-5 and p53). The rs887569 C/T SNP was
significantly associated with clinical outcome. The TT genotype predicted a
significantly longer OS in CCA patients (TT vs CT-CC p�0.026). Moreover,
the TT genotype showed a trend-like association with reduced risk of death
(HR�0.59, 95%CI�0.33-1.05, p�0.075), at multivariate analysis.
Conclusions: These results suggest the role of rs887569 EZH2 SNP as a
possible predictive marker of OS in advanced CCA patients treated with
ECX regimen, and offer a potential new tool for treatment optimization.
10613 General Poster Session (Board #51F), Mon, 1:15 PM-5:15 PM
Evaluation of circulating biomarkers of bone metastasis in early-stage
breast cancer. Presenting Author: Windy Marie Dean-Colomb, University of
Texas M. D. Anderson Cancer Center, Houston, TX
Background: Bone is the preferred site for metastasis of breast cancer,
affecting approximately 70% of women with advanced disease. N-terminal
of procollagen type 1 (P1NP), c-terminal peptide crosslinks (CTX), Osteocalcin
(OC) and interleukin-6 (IL-6) are markers of bone turnover that may
have clinical utility as predictors of breast cancer recurrence in the bone.
Methods: Serum was collected from 168 patients with stage I/II/III breast
cancer prior to treatment from 09/2001 to 12/2008 and stored at -80 C.
Serum levels of P1NP, CTX, OC and IL-6 were determined using the
Roche’s Elecsys 2010 automated immunoassay system. Correlations of
biomarker levels with time to bone metastasis (BM) development were
assessed with Cox proportional hazards regression analysis and the Kaplan-
Meier method. Results: Among the 168 patients analyzed, 60 patients
subsequently developed BM. The biomarkers all had skewed distributions
with long right tails and thus were all analyzed on the log scale. Residual
analysis suggested non-linear relationships between each biomarker and
risk of developing BM during follow-up. Thus, we fit Cox proportional
hazards regression models for each biomarker with quadratic polynomials
(on the log scale). On univariate analysis, these analyses generated p �
0.33 for IL-6, 0.26 for osteocalcin, 0.40 for CTX, and 0.032 for P1NP.
Adjusting for clinical factors (stage, age, race, post menopausal, ER/PR
status, HER2 status, nuclear grade) yielded p � 0.0035 for the quadratic
polynomial for log P1NP. A cut-point of 75 ng/mL identified patients with a
short time to development of BM. The 1, 3, and 5-year freedom-from-BM
probabilities were 96%, 77% and 66% for the 150 patients with P1NP
values � 75 ng/mL and 88%, 45%, and 36% for the 16 patients with
P1NP values � 75 ng/mL. The hazard ratio comparing patients with P1NP
values � 75 ng/mL to patients with P1NP values � 75 ng/mL was 3.0
(95% CI, 1.5 - 6.2) and p � 0.0075 ng/mL. After adjustment for clinical
factors, the hazard ratio was 3.4 (1.5, 7.6) with p � 0.0026. Conclusions:
Serum P1NP levels �75 ng/mL correlate with a shorter time to development
of BM in patients with stage I-III breast cancer.
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