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

296s Genitourinary Cancer
4577 General Poster Session (Board #1F), Sun, 8:00 AM-12:00 PM
FGFR3 protein expression and gene mutation in primary and metastatic
urothelial carcinoma (UC) tumors. Presenting Author: Jonathan E. Rosenberg,
Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute/
Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
Background: FGFR3 protein expression may represent a valid therapeutic
target in metastatic UC. The prevalence of both mutation and overexpression
is unknown in metastatic UC. Methods: Tissue microarrays of formalin
fixed paraffin-embedded urothelial carcinomas (UC) were stained for
FGFR3 by immunohistochemistry (IHC) [primary (n�250); metastatic
(n�31); of which (n�14) were paired]. FGFR3 immunostaining was scored
as negative or positive based on previously reported scoring systems.
FGFR3 mutation in primary tumors was assessed by iPlex and confirmed by
hME sequencing (n�141) or Affymetrix OncoScan FFPE Express 2.0
(primary: n�17; metastases n�31). Results: FGFR3 IHC positivity was
present in 48% of metastases (95% CI�32-65%) and 26% of primary
tumors, (95%�CI 21-32%), though strong staining was rare (�1%).
Paired primary and metastatic tumors were both negative in 50% of cases,
with 14% positive only in the metastasis, 14% positive only in the primary
tumor, and 21% positive in both. If the primary tumor showed staining,
71% of the metastases showed staining. FGFR3 IHC staining did not
impact overall survival (p�0.8). FGFR3 mutations were observed in 9.6%
of metastatic tumors (95% CI�3.3-25%), compared to 3.5% of primary
tumors (95% CI�1.5%-8%). Co-occurrence of mutation and FGFR3 DNA
copy number gain was observed in one specimen. Conclusions: FGFR3 IHC
staining is present 26 % of primary tumors of patients who go on to develop
metastatic disease, and nearly half of metastatic tumor sites. FGFR3
mutation frequency in primary and metastatic tumor specimens is low.
Further investigation of the frequency of FGFR3 protein expression in
metastases is needed. The presence of FGFR3 protein by IHC staining in
primary and metastatic specimens suggests that FGFR3 may represent a
therapeutic target even in the absence of mutation. Further functional
studies are needed.
4579 General Poster Session (Board #2A), Sun, 8:00 AM-12:00 PM
BRCA1, RAP80, and AEG-1 mRNA expression in resectable muscleinvasive
bladder cancer (MIBC) patients (p) treated with neoadjuvant
cisplatin-based chemotherapy. Presenting Author: Albert Font Pous, Institut
Catala d’ Oncologia, Hospital Germans Trias i Pujol, Badalona, Spain
Background: Cystectomy remains the standard treatment in MIBC and only
a minority of p are treated with neoadjuvant chemotherapy, suggesting that
predictive markers of chemotherapy outcome are needed. Low BRCA1
mRNA expression is associated with an improvement in survival in bladder
cancer p treated with cisplatin-based chemotherapy. However, BRCA1
function can be modulated by other DNA repair genes. RAP80 is required
for the accumulation of BRCA1 to sites of DNA breaks, and cells depleted
of RAP80 exhibit hypersensitivity to irradiation. AEG-1 can induce BRCA1
expression and cause chemoresistance. Methods: Paraffin-embedded pretreatment
tumor samples were collected by transurethral resection from 65
p with resectable MIBC stage T2-4N0M0 treated with neoadjuvant cisplatinbased
chemotherapy. Gene expression levels of BRCA1, RAP80 and AEG-1
were quantified by real-time quantitative PCR. Expression levels were
divided into terciles and correlated with median survival (MS). Results: 33 p
were treated with cisplatin, methotrexate and vinblastine (CMV) and 32 p
with cisplatin and gemcitabine. Chemotherapy was followed by cystectomy
in 60 p. Overall MS was not reached and 5-year survival was 51%. MS was
45 months (m) and 5-year survival was 27% in 21 p with high BRCA1
mRNA levels vs 168 m and 59% in 44 p with low and intermediate levels
(p�0.05). MS was 50 m in 15 p with high AEG-1 levels, 45 m in 15 p with
intermediate levels, and was not reached in 18 p with low levels, although
these differences were not statistically significant (p�0.3). No differences
in MS were observed according to RAP80 mRNA levels. Conclusions:
BRCA1 can be a useful marker to predict the efficacy of neoadjuvant
chemotherapy. Cisplatin-based chemotherapy should be recommended in
p with low/intermediate BRCA1 expression. Further studies with larger
numbers of p are warranted to elucidate the role of AEG-1 in this setting.
4578 General Poster Session (Board #1G), Sun, 8:00 AM-12:00 PM
A pre-cystectomy decision model to predict pathologic upstaging and
oncologic outcomes in clinical stage T2 bladder cancer. Presenting Author:
Siamak Daneshmand, University of Southern California Keck School of
Medicine and Norris Comprehensive Cancer Center, Los Angeles, CA
Background: Neoadjuvant chemotherapy is the standard for advanced
bladder cancer (BC), although its benefit in lower risk clinically organconfined
muscle-invasive (cT2N0M0) BC is uncertain. This study aimed to
define pre-cystectomy factors in cT2N0M0 BC that could predict pathological
upstaging at cystectomy and oncological outcomes. Methods: 1,964
institutional BC patients were reviewed. Neoadjuvant chemotherapy-naïve
cT2N0M0 patients who underwent cystectomy were included. A multivariate
classification and regression decision tree was used to assess hierarchical
interactions of univariately significant variables, thereby identifying
patients at greatest risk for upstaging and poor outcome. Results: 948
cT2N0M0 patients were identified; 512 (54%) were upstaged at cystectomy.
Pathological upstaging was associated with poor RFS and overall
survival (OS) (both p � 0.001). Age, lymphovascular invasion (both P �
0.01), multifocality (p � 0.004), deep muscle invasion, tumor growth
pattern and hydronephrosis (all p � 0.001) were associated with upstaging.
When these factors were included in a multivariate decision tree
model, 71% of patients with hydronephrosis were upstaged and had the
worst outcome (p � 0.001). In patients without hydronephrosis, tumor
growth pattern was a second-tier discriminator; only 37% of patients with
papillary tumors were upstaged. In patients with non-papillary tumors,
deep muscle invasion was a third-tier discriminator; 70% of patients with
invasion were upstaged. Age was a third-tier discriminator in patients with
papillary � non-papillary features; 33% of patients �65 years were
upstaged compared to 47% of patients �65 years. The decision tree was
cross-validated and resulted in 3 risk groups – 5 year RFS/OS for low risk
patients was 66%/48% versus 46%/27% for high risk patients (p �
0.001). Conclusions: This study identified pre-cystectomy variables that
predict upstaging and poor outcomes in cT2N0M0 BC. The decision tree
approach highlighted the most crucial prognostic variables, and can aid in
identifying low risk patients in a stepwise fashion who have lower probability
of upstaging and better outcomes.
4580 General Poster Session (Board #2B), Sun, 8:00 AM-12:00 PM
Multidimensional investigation of HER2 in advanced urothelial carcinoma
(UC). Presenting Author: Rachel S. Park, Lank Center for Genitourinary
Oncology, Dana-Farber Cancer Institute, Boston, MA
Background: Incidence of Her2 positivity and association with overall
survival (OS) are controversial in advanced UC. Activating Her2 mutations
have been identified in other cancers, but they have not been previously
reported in UC. We determined Her2 status by immunohistochemistry
(IHC), fluorescence in situ hybridization (FISH), and copy number gain
(CNG) via array CGH of primary UC tumors from patients (pts) with
metastatic disease. Targeted Her2 sequencing was performed at known
mutation hotspots, and mutation effect was investigated in vitro. Methods:
Tissue microarrays of formalin fixed paraffin-embedded tumor from 98 UC
pts treated with platinum-based combination chemotherapy for metastatic
disease were evaluated for Her2 protein and for Her2 gene amplification by
using standard clinical protocols. Positive staining was defined as an IHC
score of 3� or a FISH ratio of �2 using scoring criteria established for
evaluation of breast cancer. Her2 CNG was evaluated by aCGH with cutoff
log base 2 ratio � 0.9. Mutation status was validated by hME sequencing.
OS was measured from start of treatment for metastatic disease. Association
of OS and Her2 status was assessed by a Cox regression model.
NIH-3T3 cells with Her2 V777L were assessed for growth, invasion, and
Her2 kinase activation. Results: 22% of pts had 3� Her2 staining by IHC.
21% of pts had FISH amplification. These were concordant in 78% of pts.
CNG was identified in 16% and was concordant with FISH and IHC 85%
and 88% of the time, respectively. Her2 status by any modality showed no
significant association with OS in either univariate [HR�0.94, 95% CI:
(0.52, 1.70), p�0.83] or multivariate [HR�1.12, 95% CI: (0.61, 2.06),
p�0.72] analysis. Her2 mutations (V777L and L755S) were identified in 2
pts (2%). In vitro analysis of V777L results in transformation of NIH-3T3
cells, leading to increased growth, invasion on soft agar, and Her2 kinase
constitutive activation. Conclusions: Her2 overexpression or amplification
in the primary tumor does not predict OS in pts with metastatic UC. Other
research has suggested that V777L sensitizes cells to lapatinib, while
L755S leads to lapatinib resistance. These rare oncogenic Her2 mutations
occur and may be therapeutic targets in selected pts.
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