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

4067 General Poster Session (Board #44B), Mon, 8:00 AM-12:00 PM
Correlation between overall survival and other endpoints in clinical trials of
second-line chemotherapy for patients with advanced gastric cancer.
Presenting Author: Kohei Shitara, Aichi Cancer Center Hospital, Nagoya,
Japan
Background: The correlation between progression-free survival (PFS) or
time to progression (TTP) and overall survival (OS) has been evaluated in
patients with advanced gastric cancer (AGC) who received first-line
chemotherapy (Shitara, K et al. Invest New Drug 2011; Shitara K and
Burzykowski T, et al, ASCO 2011). However, no corresponding analysis had
been done in patients who underwent second-line chemotherapy for AGC.
Methods: We evaluated the potential of PFS, TTP, response rate (RR), or
disease control rate (DCR) to act as surrogates for OS in phase II and III
trials of second-line chemotherapy for AGC by comprehensive literaturebased
analysis. Correlations between each endpoint and OS were evaluated
by Spearman rank correlation coefficient (�). Subgroup analyses by trial
region or type of failure to previous chemotherapy were also conducted.
Results: Fifty-six trials, including four randomized studies, were selected
for analysis and covered a total of 61 treatment arms and 3,038 patients;
34 studies were conducted in Asia, 20 studies in Non-Asian countries, and
two studies in both regions. Median PFS were similar in Asian and
Non-Asian trials (3.0 vs. 3.3 months). In contrast, median OS tended to be
longer in Asian vs. Non-Asian trials (8.0 vs. 6.0 months; p�0.01). Median
PFS/TTP and OS showed a moderate correlation with � of 0.51 (95% CI,
0.31-0.73). Correlation tended to be higher in PFS (� � 0.62) than TTP (�
� 0.29) and higher in non-Asian trials (� � 0.73) than Asian trials (� �
0.32). Correlation between PFS/TTP and OS among the trials in which
eligibility required failure to previous fluorouracil and cisplatin also showed
low correlation (� � 0.48). The RR and DCR also did not show high
correlation with OS (� � 0.30 for RR; 95% CI 0.04-0.56; � � 0.53 for
DCR; 95% CI 0.31-0.75). The hazard ratio (HR) of PFS and OS in each
arms of the four randomized studies showed a low correlation with � of
0.10. Conclusions: Our results indicate that PFS/TTP, RR, and DCR did not
correlate sufficiently with OS to be used as surrogate endpoints in patients
with AGC who underwent second-line chemotherapy. Further research is
needed based on individual patient data from ongoing randomized trials.
4069 General Poster Session (Board #44D), Mon, 8:00 AM-12:00 PM
Customization of treatment for patients with esophageal adenocarcinoma
(EAC) who achieve clinical complete response (cCR) after chemoradiation
using initial standardized uptake value (iSUV) of 18f-fluorodeoxyglucose PET. Presenting Author: Akihiro Suzuki, University of Texas M. D. Anderson
Cancer Center, Houston, TX
Background: Patients with localized esophageal adenocarcinoma (EAC)
receive preoperative chemoradiation followed by surgery (trimodality [TM]
therapy) or definitive chemoradiotherapy (bimodality [BM] therapy) based
on comorbidities and tumor geography. However, we cannot individualize
recommendations beyond these parameters. We hypothesized that iSUV
could customize therapy. Methods: Data source was our prospective
database of fully staged EAC patients (2002-2010). All patients had a cCR
(post-chemoradiation negative biopsy and post-chemoradiation physiologic
uptake on PET). iSUV cut-point was derived by recursive partitioning.
Results: For 323 cCR patients, the median follow-up was 40.8 months. 206
(63.8%) patients had TM and 117 (36.2%) had BM therapy. Median OS of
TM patients and BM patients were 94.8 months (95 % CI; NA-NA) and
36.5 months (95% CI; 30.5-42.4; p�0.001), respectively. Similar differences
were observed in RFS (p�0.001). The median iSUV was 9.4 (range,
0-58.0). Intriguingly, TM patients with iSUV of �6 had a better OS (94.8
months; 95% CI; 39.1-150.5) and RFS (94.8 months; 95% CI; 18.2-
171.4) compared to BM patients with iSUV of �6 OS (31.4 months; 95%
CI; 21.0-41.9; p��0.001) and RFS (17.2 months; 95% CI; 14.5-19.8;
p�0.001). However, the prognosis of TM and BM cCR patients with iSUV
�6 was similar (OS, p�0.62 and RFS, p�0.46). The pathological CR
(pathCR) rate in TM patients was similar irrespective of iSUV of �6
(27.1%) vs. iSUV �6 (28.6%; p�0.85). Conclusions: Our unique data
provide an insight into the fate of cCR EAC patients by iSUV. Patient with
iSUV �6 dramatically benefit from surgery and TM therapy is encouraged.
iSUV and pathCR do not correlate. iSUV can customize therapy of localized
EAC patients.
Gastrointestinal (Noncolorectal) Cancer
255s
4068 General Poster Session (Board #44C), Mon, 8:00 AM-12:00 PM
Measuring transcripts of components of the BRCA1 DNA repair pathway,
components of the hippo-YAP pathway, �-TrCP, HER2, AEG-1, EZH2 and
other genes in advanced gastric cancer. Presenting Author: Jia Wei,
Nanjing Drum Tower Hospital, Nanjing, China
Background: The primary goal of this study was to classify gastric cancer in
two different sub-groups. We speculated that HER2-positive gastric cancers
could be regulated by �-TrCP, while tumors unaffected by �-TrCP
activation could be more dependent on the Hippo-YAP signaling pathway,
in which TAZ increases the expression of AXL. Gastric cancer can
overexpress AEG-1 and EZH2. The relationship between EZH2 and the
Hippo-YAP pathway was explored in this study. We also explored BRCA1
complexes, including upstream components, such as 53BP1 and MMSET.
Methods: Paraffin-embedded samples were collected from 132 advanced
gastric cancer patients (p) treated with first-line FOLFOX, 58 of whom
received second-line docetaxel-based treatment. Gene expression levels of
HER2, �-TrCP, TAZ, AXL, EZH2, AEG-1, BRCA1, and genes involved in
DNA repair pathways (RAP80, PIAS1, PIAS4, MDC1, 53BP1, MMSET,
and UBC9) were quantified by real-time PCR. BIM, IDO, and SPINK1 were
also examined. Results: A close correlation was found for the majority of the
genes, for example, BRCA1-MMSET (rho�0.28; P�0.002) and AXL-TAZ
(rho�0.58; P�0.001). Median overall survival (OS) was 12.5 months (m).
Among the 58 p receiving second-line docetaxel, in p with high levels of
BRCA1, OS was 24.9 m, while it was 19.1 m in p with intermediate levels
and 9.5 m in p with low levels (P�0.009). OS was 28.6 in p with high
levels of MMSET, 13.8 in p with intermediate levels and 12.3 in p with low
levels (P�0.001). In the multivariate analysis, only BRCA1 was a significant
marker for OS (Table). Conclusions: The study showed the predictive
value of BRCA1, which could be useful for customizing chemotherapy with
or without docetaxel. In addition, MMSET requires further study since it is
involved in DNA repair upstream of BRCA1.
HR 95% CI p
�-TRCP
1.22 1 Ref.
ERBB2
19.86 1 Ref.
AEG-1
1.12 1 Ref.
BRCA1
7.62 1 Ref.
4070 General Poster Session (Board #44E), Mon, 8:00 AM-12:00 PM
Investigatory study of biomarkers for gastric cancer based on a cDNA bank.
Presenting Author: Takashi Oshima, Gastroenterological Center, Yokohama
City University, Yokohama, Japan
Background: We have constructed a cDNA bank using mRNA extracted from
frozen specimens of gastric cancer tissue and adjacent normal gastric
mucosa and studied biomarkers for the individualized therapy of gastric
cancer and the identification of new treatment targets. We report currently
available results. Methods: We studied 227 patients in whom at least 5
years had elapsed since surgery for gastric cancer. The disease stage was IB
in 29 patients, II in 66, III in 103, and IV in 29. Among the 139 patients
who postoperatively received fluoropyrimidine anticancer agents, 82 with
stage II or III disease were given adjuvant chemotherapy with S-1. A total
116 genes were selected as candidate biomarkers on the basis of the
results of comprehensive DNA microarray analysis, extraction from a serial
analysis of gene expression (SAGE) database, and other studies. The
relative expression levels of these 116 genes in gastric cancer tissue and
adjacent normal mucosa were measured in each case by a quantitative
polymerase chain reaction assay using the cDNA databank described
above, and the relations between clinical histopathological factors and
treatment outcomes were examined. Results: In patients who underwent
gastrectomy, high expression levels of the secreted protein acidic and rich
in cysteine (SPARC), sulfatase 1 (SULF1), and inhibin, beta A (INHBA)
genes were significantly associated with poor outcomes. In patients with
stage II or III disease who received adjuvant chemotherapy with S-1, high
expression levels of the insulin-like growth factor receptor 1 (IGF-1R),
KIAA1199, thymidylate synthase (TS), and regenerating IV (Reg IV) genes
were significantly associated with poor survival. Conclusions: Investigatory
studies using a cDNA bank of biomarkers for gastric cancer suggested that
expression levels of the SPARC, SULFI, and INHBA genes are useful
prognostic factors in patients who undergo gastrectomy for gastric cancer.
Expression levels of the IGF-1R, KIAA1199, TS, Reg IV, and INHBA genes
may be useful biomarkers in patients who receive adjuvant chemotherapy
with S-1.
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