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

5034 Poster Discussion Session (Board #23), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Use of HE4 and CA125 to predict surgical outcome and for prognostic
value for progression-free survival (PFS) and overall survival (OS) in primary
epithelial ovarian cancer (EOC) patients (pts). Presenting Author: Ioana
Braicu, Charité University Department of Gynecology, Campus Virchow
Clinic , Berlin, Germany
Background: Optimal surgical cytoreduction and response to platinum (P)
based chemotherapy (ChTh) remain the cornerstones of therapeutic management
of primary EOC. Aim of this study was to analyze the predictive
role of HE4 and CA125 as biomarkers (BM) for clinical outcome in primary
EOC pts at diagnosis and during subsequent follow-up. Methods: In the
European OVCAD project 275 pts with primary EOC were enrolled. Pts were
eligible if radical cytoreductive surgery and P-based ChTh were applied.
Plasma collected at first diagnosis and 6 months after 1st line ChTh in
P-sensitive pts was analyzed for HE4 and CA125 levels using ELISA and
Luminex technique, respectively. Results: Complete cytoreduction with no
residual tumor disease (RTD) was obtained in 69.9% pts. HE4 and CA125
expression in plasma at first diagnosis correlated with RTD, p � 0.002 and
p�0.002, respectively. The sensitivity (SE) and specificity (SP) of the
combinative use of both BM in predicting RTD was 64.8% and 73.5%,
respectively. Pts having over-expression of both BM in plasma had a 6.1
greater risk for RTD (p�0.001, OR: 6.107, 95% CI 2.41-15.46). Presistance
occurred more frequently when both BM were over-expressed
(p�0.028, OR� 3.1, 95%CI 1.13-8.46). Elevated BM levels during
follow-up predicted recurrence (SE 90% and SP 71% for CA125 �55U/
ml; SE 72.7% and SP 81.4% for HE4 �150pM) and when HE4 or CA125
were positive, a SE of 86.4% and SP of 72.9% were achieved. Elevated
CA125 and HE4 at 6 months following adjuvant therapy was associated
with significantly poorer PFS (p�0.001, HR 9.6, 95%CI 3.93-23.44 with
elevated HE4 or CA125, and HR�50.52, 95%CI 14.44-176.78, with
elevated HE4 and CA125) and OS (p�0.001, HR�7.42 95%CI 1.43-
38.42 with elevated HE4 or CA125 and HR�28.38 95%CI 6.50-123.97
with elevated HE4 and CA125). Conclusions: The combinative use of HE4
and CA125 appears to have a significant value in predicting optimal
surgical outcome and development of P resistance disease in EOC pts.
Elevated plasma levels 6 months after 1st line ChTh significantly correlate
with OS and PFS in P-sensitive pts.
5036 Poster Discussion Session (Board #25), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Use of an optimized primary ovarian cancer xenograft model to mimic
patient tumor biology and heterogeneity. Presenting Author: Zachary C.
Dobbin, University of Alabama at Birmingham, Birmingham, AL
Background: Current xenograft and transgenic models of ovarian cancer are
mainly homogeneous and poorly predict response to therapy. Use of patient
tumors may represent a better model for tumor biology and offer potential to
test personalized medicine approaches, but poor take rates and questions
of recapitulation of patient tumors have limited this approach. We have
developed a protocol for improved feasibility of such a model and examined
its similarity to the patient tumor. Methods: Under IRB and IACUC approval,
23 metastatic ovarian cancer samples were collected at the time of tumor
reductive surgery. Samples were implanted either subcutaneously (SQ),
intraperitoneally (IP), in the mammary fat pad (MFP), or in the subrenal
capsule (SRC) and monitored for tumor growth. Cohorts from 8 xenolines
were treated with combined carboplatin and paclitaxel or vehicle, and
response to therapy compared between xenografts and patients. Expression
of tumor-initiating cell (TIC) markers ALDH1, CD133, and CD44 was
assessed by immunohistochemistry in tumors from patients and treated
and untreated xenografts. Results: At least one SQ implanted tumor
developed in 91.3% of xenografts, significantly higher than in the MFP
(63.6%), IP (23.5%), or SRC (8%). Xenografts were similar in expression
of putative TIC’s compared to patient tumors. The patients and the
xenografts also have similar responses to chemotherapy in that xenografts
from patients with a partial response responded more slowly than those
from patients achieving a complete response (45 vs 21 days, p�.004).
Treated xenografts were more densely composed of TICs. ALDH1 increased
to 36.1% from 16.2% (p�0.002) and CD133 increased to 33.8% from
16.2% (p�0.026). Conclusions: Xenoline development can be achieved at
a high rate when tumors collected from metastatic sites are implanted SQ.
These xenografts are similar to patient tumors with regard to chemotherapy
response and TIC expression.. This model may be a more accurate model
for in vivo pre-clinical studies as compared to current models. Also, as
treated xenografts become chemoresistant, this model is well positioned to
evaluate targeted therapies aimed at the most aggressive populations in a
heterogeneous tumor.
Gynecologic Cancer
335s
5035 Poster Discussion Session (Board #24), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Functional profiling of clear cell ovarian cancer. Presenting Author: Rowan
Miller, The Institute of Cancer Research, London, United Kingdom
Background: Clear cell ovarian cancer represents up to 15% of epithelial
ovarian cancers. In comparison to other subtypes, clear cell ovarian
carcinomas have a poorer prognosis and are relatively resistant to standard
platinum based chemotherapy. Recently, loss of function mutations in the
tumour suppressor gene ARID1A were identified in up to 50% of ovarian
clear cell carcinomas. We have adopted an integral functional and
molecular profiling approach as a route to identify new genetic dependencies
and therapeutic targets for this disease. Methods: Clear cell ovarian
cancer cell lines were functionally profiled using high throughput screening
with chemical and siRNA libraries. This has been integrated with molecular
profiling data generated from exome and transcriptome sequencing to aid
the discovery of novel targets. Results: Using functional screens we have
now identified critical gene dependencies and potential therapeutics in a
series of clear cell ovarian cancer models. The comparison of functional
viability profiles for models characterized by ARID1A loss of function
mutations is now enabling an analysis of synthetic lethal effects that could
be used to target clear cell ovarian cancers carrying these mutations.
Conclusions: The work undertaken so far provides the framework for the
discovery of therapeutic targets for clear cell ovarian cancer using an
integrated approach. Revalidation of these preliminary results is now
underway to characterize new genetic dependencies for this disease.
5037 General Poster Session (Board #17E), Sun, 8:00 AM-12:00 PM
Effect of weekly administration of bevacizumab, gemcitabine, and oxaliplatin
in patients with heavily pretreated ovarian cancer. Presenting Author:
Yuji Ikeda, Ohki Memorial Cancer Center for Women, Tokorozawa, Japan
Background: The combination therapy of gemcitabine with oxaliplatin
(GEMOX) has high activity in patients with ovarian cancer. Bevacizumab
(B), a vascular endothelial growth factor specific antibody, enhances
chemotherapeutic efficacy through its anti-angiogenic function in various
types of tumors. We evaluated the effect of weekly administration of B and
GEMOX in heavily-pretreated patients with recurrent or refractory ovarian
cancers (ROC). Methods: Nineteen patients with ROC received at least three
or more cycles of weekly-B and GEMOX consisting of B (2mg/kg),
gemcitabine (300mg/m2 ) and oxaliplatin (30mg/m2 ). The treatment was
continued until the development of progressive disease. The response and
adverse effects (AE) were evaluated using the response evaluation criteria
in solid tumors (RECIST), CA125 Gynecologic Cancer Intergroup (GCIG)
criteria, and common terminology criteria for adverse events (CTCAE)
version 3.0. Results: Seventeen (89%) of the 19 patients were primarily
stage 3 or 4. Fifteen patients (79%) had received more than three regimens
of chemotherapy. All patients were pretreated with a platinum-containing
regimen within 6 months and 16 of these patients (84%) were pretreated
within 3 months. According to the RECIST evaluation, 2 patients (11%)
had a complete response (CR), 6 patients (32%) had a partial remission
(PR) and 5 patients (26%) had a stable disease (SD). The response rate
(RR; CR�PR) and clinical benefit rate (CBR; CR�PR�SD) were 42% and
68%, respectively. In 10 patients with serous adenocarcinoma, RR was
60%. In 6 patients pretreated with weekly B and pegylated liposomal
doxorubicin (PLD), RR was 50%. Median progression-free survival was 5
months (range: 2-11 months). Hematological adverse effects (AE) with
grade 3/4 were leukopenia (16%), neutropenia (10%), thrombocytopenia
(5%), however, all AE were manageable. Conclusions: Weekly B and
GEMOX administration had significant activity with mild AE in patients with
ROC especially in serous adenocarcinoma. Notably, the activity was also
observed in patients pretreated with weekly B and PLD. These results
warrant further prospective study.
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