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

4008 Oral Abstract Session, Sat, 3:00 PM-6:00 PM
A randomized controlled phase II study of the prophylactic effect of
urea-based cream on the hand-foot skin reaction associated with sorafenib
in advanced hepatocellular carcinoma. Presenting Author: Zhenggang Ren,
Zhongshan Hospital, Fudan University, Shanghai, China
Background: Sorafenib (SOR) has become the standard treatment for
advanced hepatocellular carcinoma (HCC). Hand-foot skin reaction (HFSR)
is one of the most common adverse events associated with SOR and its
occurrence can impact patient quality of life and lead to dose modification
or interruption, both of which may negatively impact clinical outcomes.
This randomized controlled trial is the first large prospective study to
investigate the prophylactic effect of urea-based creams on HFSR associated
with SOR. Methods: Patients with advanced HCC treated with SOR
were randomly assigned 1:1 to receive prophylactic urea-based cream (Arm
A) or best supportive care (BSC) following development of HFSR (Arm B).
SOR was administered 800 mg daily. Urea-based cream was given twice
daily for up to 12 weeks starting on Day 1. BSC was at the physician’s
discretion and excluded urea-based creams. The primary endpoint was the
incidence of all-grade HFSR in the first12 weeks. Results: Eight hundred
sixty eight patients were enrolled; 439 patients in Arm A and 432 patients
in Arm B. There was no difference of baseline characteristics between two
arms. Over the 12 week period of study, the incidence of all-grade HFSR
was significantly lower in Arm A compared to Arm B; n�246 (56.0%)
patients in Arm A versus n�318 (73.6%) patients in Arm B, p�0.0001.
The incidence of grade �2 HFSR tended to be lower in Arm A compared to
Arm B, but did not reach statistical significance; n�96 (21.9%) patients
Arm A versus n�126 (29.2%) patients in Arm B, p�0.1638. The median
time to the first HFSR event was 2.5 fold longer in Arm A compared to Arm
B; 84 days (95% CI 45-93 days) in Arm A and 34 days (95% CI 29-43
days) in Arm B (p�0.001). Conclusions: This is the first large prospective,
randomized control trial examining the prophylactic use of urea-based
creams for treatment of HFSR associated with a multikinase inhibitor.
Compared to BSC, prophylactic topical use of a urea-based cream appears
to be effective in preventing and/or delaying the incidence of HFSR
associated with SOR treatment in patients with advanced HCC.
4010 Poster Discussion Session (Board #2), Mon, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Assessment of HER2 gene amplification in adenocarcinomas of the
stomach or gastroesophageal junction in the INT-0116/SWOG9008 clinical
trial. Presenting Author: Michael Alexander Gordon, Keck School of
Medicine of the University of Southern California, Norris Comprehensive
Cancer Center, Los Angeles, CA
Background: Trastuzumab has been approved for treatment of patients with
HER2-positive metastatic gastric carcinoma; however, relatively little is
known about the role of HER2 in the natural history of this disease.
Methods: Patients enrolled in the INT-0116/SWOG9008 phase III gastric
cancer clinical trial (n�559) were retrospectively evaluated for HER2 gene
amplification by fluorescence in situ hybridization (FISH)(n�258), overexpression
by immunohistochemistry (IHC)(n�148) and HER2 amplification
by silver-enhanced in situ hybridization (n�77) based on availability of
tissue specimens. The purpose of the original clinical trial was to evaluate
the benefit of post-operative 5-fluorouracil/leucovorin plus radiation therapy
compared to surgery alone. Results: HER2 gene amplification rate by FISH
was 10.9% in tumor tissue from 258 patients evaluated. HER2 status
determined by FISH was 92% concordant with SISH. HER2 overexpression
rate by IHC was 12.2% among 148 patients evaluated, with 90%
agreement between FISH and IHC. There was a significant interaction
between HER2 status by FISH and treatment with respect to both OS
(p�0.034) and DFS (p�0.020). Among patients with HER2 non-amplified
cancers, treated patients had a median OS of 44 months compared to 24
months for patients in the surgery only arm (34 and 17 months respectively
for DFS, p�0.003). Among 28 patients with HER2 amplified cancers, the
medians for OS were 16 months in the treated arm, and 22 months in the
surgery arm (p�0.55) (13 and 11 months respectively for DFS, p�0.87).
We were unable to detect a statistically significant treatment benefit in this
small subset of patients with HER2 amplification. HER2 amplification
status was not an independent prognostic marker of OS among patients
who received no postoperative chemotherapy or radiation therapy (p�0.76).
Conclusions: Patients lacking HER2 amplification responded significantly
to treatment as indicated by both OS and DFS.
Gastrointestinal (Noncolorectal) Cancer
241s
4009 Poster Discussion Session (Board #1), Mon, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Adverse prognostic impact of heterogeneous HER2 gene amplification in
patients with esophageal adenocarcinoma (EAC). Presenting Author: Harry
H. Yoon, Mayo Clinic, Rochester, MN
Background: HER2 expression in upper digestive cancer is reported to be
heterogeneous, which substantially affects interpretation of HER2 positivity
in the clinic. Yet the frequency and prognostic impact of HER2 genetic
heterogeneity and polysomy 17 (poly17) are unknown in EAC. Methods:
HER2 amplification (fluorescence in situ hybridization) and protein expression
were examined in untreated surgical EAC specimens (N � 661) at
Mayo Clinic. HER2 genetic heterogeneity was defined per ASCO/CAP as
amplification (HER2/CEP17 ratio � 2) in 5-50% of cancer cells; poly17
refers to � 3 copies of chromosome 17. Most tumors were T3-4 (68%) or
lymph node (LN)-positive (73%). Cox models were used to assess diseasespecific
(DSS) and overall survival (OS). Results: HER2 amplification was
detected in 117 of 661 EACs (18%), of which 20 (17%) showed HER2
heterogeneity. HER2 heterogeneous tumors had a significantly higher
frequency of poly17 and high tumor grade. HER2 heterogeneity by
amplification vs expression were correlated. Since heterogeneity was
limited to HER2-amplified tumors, survival analysis was stratified by
amplification status. In multivariable analysis, only HER2 heterogeneity
and metastatic LN number were prognostic (Table). Conclusions: Among
HER2 amplified EACs, 17% show HER2 heterogeneity, which is associated
with increased poly17 and independently predicts 2-fold higher risk of
cancer-specific death. Among HER2-nonamplified cases, poly17 is independently
associated with worse survival. These novel findings demonstrate
aggressive subgroups in HER2-amplified and -nonamplified EACs that have
important implications for HER2 analysis and evaluation of benefit from
HER2 targeted therapy.
DSS
Variable
a OS a
HR p HR p
HER2-amplified N � 117
Heterogeneity, yes vs no 2.0b 0.025 2.0c 0.026
Grade, 4 v 1-3 1.1 0.7 1.1 0.8
T stage, 3-4 v 1-2
No. LN
1.3 0.2 1.3 0.3
d 1.1 �.001 1.4 �.001
Poly17, yes v no
HER2-nonamplified N � 544
0.7 0.1 0.7 0.1
Heterogeneity None
Grade, 4 v 1-3 1.3 0.01 1.3 0.007
T stage, 3-4 v 1-2
No. LN
2.0 �.001 1.9 �.001
d 1.1 �.001 1.1 �.001
Poly17, yes v no 1.4 0.012 1.3 0.023
a Adjusted for all covariates; b 95% confidence interval (CI) 1.1 – 3.8; c 95% CI 1.1 – 3.7; d Per metastatic LN.
HR, hazard ratio.
4011 Poster Discussion Session (Board #3), Mon, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Profiling of activated receptor tyrosine kinases in advanced gastric cancers
identifies patients with poor prognosis. Presenting Author: Phillip Sangwook
Kim, Prometheus Laboratories Inc., San Diego, CA
Background: Metastatic gastric cancer (GCA) remains a therapeutic challenge
due to its poor prognosis. Trastuzumab is the only known targeted
therapy that has demonstrated a survival benefit in a small subset of
metastatic GCAs. Addition of molecular diagnostics for predicting prognosis
and therapeutic outcomes can significantly enhance the clinical
management of GCAs. Herein, we identify activated receptor tyrosine
kinases (RTKs) in distinct GCA subsets that correlate with disease-free
survival post-curative GCA surgery. Methods: Fresh frozen GCA tissues from
434 stage I to IV GCA patients were profiled for HER1, HER2, HER3,
p95HER2, c-MET and IGF1R RTKs using the multiplexed Collaborative
Enzyme Enhanced Reactive (CEER) immunoassay. CEER is a highly
sensitive and specific proximity assay that relies on the formation of a triple
antibody complex surrounding the target protein. Results: p95HER2, a
known trastuzumab resistance mechanism, was identified for the first time
in 79% of IHC/FISH-based HER2(�) GCAs. Full-length HER2 expression
was heterogeneous with ~20% of HER2(-) GCAs still expressing the HER2
protein. 232/434 GCAs expressed at least one activated RTK analyzed in
our study. Of these 232 patients, 121 patients that presented with stage II
or III disease at the time of surgery; demonstrated a worse progression-free
survival as compared to those where none of the analyzed RTKs were
activated (32.6 months vs 76.5 months, p�0.0318). HER axis members
were the most commonly activated RTKs with 64% of such GCAs.
Approximately 71% of activated cMET tumors demonstrated a coactivation
with a HER axis member with a preference for HER1 in ~61% of
cMET-activated GCAs. Patients with p-MET(�):p-HER1(�) GCAs had a
worse prognosis as compared to those with p-MET(�):p-HER1(-) GCAs
(46.2 months vs 82.8 months, p�0.0184). Conclusions: CEER-based RTK
characterization revealed concomitantly activated signaling pathways in
GCAs which could predict disease recurrence. Comprehensive molecular
profiles of GCA tumors can allow for the implementation of these companion
biomarkers in GCA therapeutic clinical trials.
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