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

4646 General Poster Session (Board #10E), Sun, 8:00 AM-12:00 PM
Polymorphisms in fragile histidine triad gene (FHIT) associated with
aggressive prostate cancer and cancer specific mortality. Presenting
Author: Yan Ding, City of Hope, Duarte, CA
Background: FHIT is a 1.5 Mb gene encoding a 16.8 kD triphosphatase
known to promote apoptosis responding to DNA damage in epithelial cells.
It resides in the most frequently observed fragile site in the human genome,
FRA3B, and is frequently deleted in early development of multiple cancer
types. More importantly, down regulation of FHIT protein has been
associated with clinical features of tumors, such as the presence of
extraprostatic extension and Gleason Score � 8 in prostate cancer (CaP),
advanced diseases in breast cancer, and shorter survival after platinumbased
treatment for advanced non-small cell lung cancer. Previously, a
genetic locus for CaP has been reported in FHIT. Here we evaluated
association of aggressive CaP and death due to CaP with Single nucleotide
polymorphisms (SNPs) in FHIT using cases and controls of European origin
nested in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer
Screening trial with 13 years of follow-up. Methods: We analyzed 659 SNPs
on FHIT in 1,164 CaP patients (476 with nonaggressive CaP, Gleason � 7
and stage � III; 688 with aggressive CaP, Gleason �� 7 and/or stage III/IV;
63 with death due to CaP) and 1,167 controls using an incidence density
sampling strategy. Stratified Cochran-Mantel-Haenszel test and logistic
regression were performed to test association. Results: We detected
significant association (p � 0.05) of incident CaP to 48 SNPs and
aggressive CaP to 52 SNPs. After 50,000 permutations, two SNPs within a
7 kb region, one for incident CaP and the other for aggressive CaP,
remained marginally significant (corrected p � 0.053 and 0.093, respectively).
The same risk allele for aggressive CaP was also associated with
CaP-specific mortality (OR � 1.50, p � 0.027). The association was
stronger after adjusting for Gleason, stage, and PSA at diagnosis, treatment
options after diagnosis. Test on imputed SNPs within the 7 kb intronic
region identified 7 additional SNPs in 2 linkage disequilibrium groups at
higher risk to CaP-specific death (OR � 1.98, p � 0.00015 and OR �
2.51, p � 0.0027). Conclusions: Risk SNPs in FHIT were implicated for
aggressive disease and CaP specific death. Replication of these SNPs in
other populations is warranted.
4648 General Poster Session (Board #10G), Sun, 8:00 AM-12:00 PM
Overall survival (OS) benefit with sipuleucel-T by baseline PSA: An
exploratory analysis from the phase III IMPACT trial. Presenting Author:
Gerald Chodak, Weiss Memorial Hospital, Chicago, IL
Background: Sipuleucel-T is an autologous cellular immunotherapy approved
for asymptomatic or minimally symptomatic metastatic castrateresistant
prostate cancer. In the IMPACT trial, sipuleucel-T showed a
22.5% reduction in risk of death vs the control group (hazard ratio
[HR]�0.775 [95% CI 0.614, 0.979]; P�0.032). A pre-specified subgroup
analysis for baseline prognostic variables showed homogeneous
treatment effects consistently favoring sipuleucel-T. In patients (pts) with
baseline PSA below vs above the median, there was a trend toward greater
treatment effect (HR�0.685 vs. 0.865). In this exploratory analysis, we
further sub-divide baseline PSA into quartiles to evaluate potential treatment
effect patterns. Methods: The analysis included all randomized pts
from IMPACT (n�512). Pts were categorized by baseline PSA quartile
(Table), ECOG PS and by median for other baseline prognostic variables
(i.e., LDH, PAP, ALP in bone-only disease, and Hgb). Median OS and HR
were estimated using Kaplan-Meier and Cox models, respectively. Results:
Increasing baseline PSA quartile was associated with markers of advanced
disease. HRs suggest a consistent treatment effect in all subsets, although
there is inadequate power to show significant results within each quartile.
There was a trend toward an increased magnitude of treatment benefit in
pts with a lower baseline PSA (Table). Results for other baseline prognostic
variables also suggest a trend toward greater benefit in subjects with better
prognostic features. However, results for baseline Hgb indicated an
opposite trend. Conclusions: Although not adequately powered for significance,
the results of this analysis support a consistent OS benefit with
sipuleucel-T across PSA quartiles. The greater magnitude of benefit in pts
with lower baseline PSA suggests that pts with less advanced disease may
benefit more from treatment with sipuleucel-T.
Baseline PSA (ng/mL)
22.1–50.1 >50.1–134.1 >134.1
n 128 128 128 128
Median OS, months
Sipuleucel-T 41.3 27.1 20.4 18.4
Control 28.3 20.1 15.0 15.6
Difference 13.0 7.1 5.4 2.8
HR (95% CI) 0.51 (0.31, 0.85) 0.74 (0.47, 1.17) 0.81 (0.52, 1.24) 0.84 (0.55, 1.29)
Genitourinary Cancer
313s
4647 General Poster Session (Board #10F), Sun, 8:00 AM-12:00 PM
Guideline-discordant androgen deprivation therapy (ADT) use in localized
prostate cancer (CaP) and cost implications: A population-based study.
Presenting Author: Adam Rea Kuykendal, University of North Carolina at
Chapel Hill, Chapel Hill, NC
Background: ADT use in localized CaP has increased overall survival and is
recommended by National Comprehensive Cancer Network (NCCN) guidelines
in certain clinical situations. However, ADT may cause harm and is
without benefit in other situations. Prior studies showed a decline in
“inappropriate” ADT use coinciding with Medicare reimbursement changes
in 2004-2005. This study examines recent trends in ADT use and
quantifies the cost of guideline-discordant ADT. Methods: Patients in the
Surveillance Epidemiology and End Results (SEER)-Medicare database
diagnosed with non-metastatic CaP between 2004 and 2007, ages 66-80
were included for analysis. PSA, Gleason score and clinical stage were used
to define D’Amico risk categories. Logistic regression was used to examine
factors associated with guideline-discordant ADT use. Annual direct cost
was estimated using the current Medicare reimbursement amount for ADT.
Results: Of 24,280 men included, 13% received guideline-discordant ADT.
Discordant use declined from 15% in 2004 to 11% in 2007. In low-risk
patients, 15% received discordant ADT, mostly due to simultaneous ADT
with radiation. Discordant use was seen in 7% of intermediate and 16% of
high-risk patients, mostly from ADT monotherapy. African American (AA)
(p�.001), older patients (p�.001) and those with more comorbidities
(p�.001) were more likely to receive discordant ADT (Table). The estimated
annual direct cost to Medicare from discordant ADT is $43,500,000.
Conclusions: Approximately one in eight patients received ADT discordant
with published guidelines, with AA and elderly patients disproportionately
affected. Elimination of discordant use would result in substantial savings
in healthcare costs.
Covariate OR p value
AA (vs. Caucasian) 1.35 �.001
Age (vs. 65-69)
70-74 1.58 �.001
75-79 3.22 �.001
Modified Charlson comorbidity (vs. 0)
>0 1.34 �.001
Diagnosis (vs. 2004)
2005 .86 .008
2006 .78 �.001
2007 .71 �.001
Risk group (vs. low risk)
Intermediate .40 �.001
High .88 .003
Controls for SEER region, regional socioeconomic indicators, and marital status.
4649 General Poster Session (Board #10H), Sun, 8:00 AM-12:00 PM
Targeted next-generation sequencing (NGS) of advanced prostate cancer
(PCA) using formalin-fixed tissue. Presenting Author: Himisha Beltran,
Weill Cornell Medical College, New York, NY
Background: The genomic landscape of advanced PCA is not well characterized,
partly due to limited availability of frozen metastatic tissue. This has
created a gap in our knowledge of treatment related and potentially
targetable genomic alterations. The purpose of this study was to demonstrate
feasibility of performing NGS to molecularly characterize advanced
PCA using formalin-fixed paraffin embedded (FFPE) tissue. Methods: 25
metastatic CRPC, 4 metastatic hormone naïve PCA, 3 primary localized
PCA, and 18 benign matched prostates were evaluated (40mm FFPE tissue
per case). High-density foci were captured and sequenced for 3230 exons
of 182 cancer-related genes and 37 introns of 14 genes often rearranged in
cancer to an average depth of �800x in a CLIA lab (Foundation Medicine).
Recurrent mutations, copy number alterations, and fusions were validated
using PCR and FISH. Results: In �90% of samples, there was sufficient
DNA (�50 ng) for analysis. Recurrent high confidence cancer alterations in
CRPC included: TMPRSS2-ERG fusion (44%), PTEN loss (44%), TP53
mutation (40%), AR mutation (24%), AR gain (24%), RB mutation (28%),
MYC gain (12%), and BRCA2 loss (12%). Overall 48% of CRPC harbored
AR gene alterations. Additionally, there were mutations in CTNNB1 (12%),
ATM (8%) and PIK3CA (4%). Copy number alterations not previously
described in PCA included CCND1, CDK4/6 gains and CDKN2A/CDKN2B
deletions. Hormone naïve metastatic and high risk localized PCA demonstrated
similar frequency of TMPRSS2-ERG gene fusion, BRCA2 deletion,
and TP53 mutations as CRPC, but AR alterations and MYC gain were not
seen. Conclusions: This study demonstrates feasibility of in-depth, NGS
based DNA analysis using FFPE tissue, even biopsy material. Frequent AR
alterations in CRPC, mutations associated with disease progression, and
potential drug targets were identified. Focused NGS has clinical potential
to identify actionable genomic alterations in advanced PCA that can impact
patient participation in trials as well as treatment and outcome. Treatment
options include PARP inhibitors for patients with BRCA2 and ATM
alterations (20% of cases) and PI3K/AKT inhibitors for PIK3CA mutations.
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