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

298s Genitourinary Cancer
4585 General Poster Session (Board #2G), Sun, 8:00 AM-12:00 PM
External validation of somatic copy number alteration (SCNA) at chromosome
1q23.3 in advanced urothelial carcinoma (UC). Presenting Author:
Markus Riester, Department of Biostatistics and Computational Biology,
Dana-Farber Cancer Institute, Boston, MA
Background: Advanced UC is associated with multiple SNCAs. To identify
SCNA predictors of poor survival in advanced UC, we evaluated SCNAs in
two cohorts of high-risk urothelial carcinoma of the bladder. Methods: We
obtained DNA copy number data from bladder cancer patients in two
independent cohorts [Spanish cohort (n� 93, Agilent aCGH 180k array)
and Brigham and Women’s/Dana-Farber (BW/DF) cohort (n � 48, Affymetrix
OncoScan FFPE Express 2.0)]. For the BW/DF cohort, we acquired
copy number information from 30 primary tumors and 33 metastases. For
12 patients, both primary and matched metastases were available. The
GISTIC method was used on GLAD segmented data to identify driver copy
number lesions, and the NBC algorithm to identify recurrent breakpoints.
Cox proportional hazards models were used to estimate the effect of the
identified SCNAs on overall survival, defined as time from start of
chemotherapy for metastatic disease (Spanish) or from metastatic recurrence
(BW/DF). Copy numbers were incorporated in the Cox models as
continuous measures. Statistical significance of optimal cutpoints was
estimated with permutation tests. Copy number profiles of primary tumors
and metastases were compared with hierarchical clustering. Results:
Amplification of 1q23.3 was independently associated with overall survival
in both cohorts (Spanish cohort: HR 3.98; 95% 1.64-9.67; p � 0.03;
C-statistic 0.54, 95% 0.45-0.65. BW/DF cohort: HR 6.28; 95% 1.84-
21.4; p � 0.042; C-statistic 0.62, 95% 0.48-0.76). Amplifications at
22q12.2 were enriched in patients who developed metastasis (p � 0.05).
A breakpoint analysis identified possible truncations of ITPR1 (Spanish:
15%; BW/DF: 25%) and PRIM2 (Spanish: 31% BW/DF: 12.5%) in large
numbers of samples. For primary tumors with matched metastases, we
observed that metastases clustered together with their primary tumors.
Conclusions: External validation of the 1q23.3 amplification demonstrates
the association of this SCNA with poor outcomes in advanced UC; the
identification of the target of this copy number gain is ongoing. Gene
truncations and their biological significance require further experimental
investigation.
4587 General Poster Session (Board #3B), Sun, 8:00 AM-12:00 PM
Long-term progression-free survival (PFS) and overall survival (OS) to
pemetrexed (P) as single agent in metastatic urothelial carcinoma (MUC): A
Spanish Oncology Genitourinary Group (SOGUG) systematic review. Presenting
Author: J. M. Cervera Grau, ITIC Benidorm, Valencia, Spain
Background: The effect of pemetrexed in MUC is not well characterized.
Vinflunine is the standar second-line in MUC with adjusted benefits and no
more drugs have been aproved. SOGUG reports a systematic review of MUC
patient series with high activity of P in monotherapy. Methods: Patients with
locally advanced urothelial carcinoma and/or MUC whom received P 500
mg/m(2) every 21 days with folic acid and vitamin B12 supplementation,
were elected. These patients received P in second, third or fourth-line of
chemotherapy. Results: 44 patients have been reported (39males), median
age 62 [41-82]. Of all 44 patients; 21, 22, and 1 patients received P as
second-line, third and fourth-line respectively. A median of 4 courses were
administered [1-12] and disease control (SD�PR�CR) was achieved in 19
patients for an overall control rate of 43.2%. Four groups with significant
differences in PFS (p�.033) were established (1.bone-metastasis, 2.visceral-metastasis,
3. nodal-visceral-metastasis and 4.nodal-metastasis). OS
was significant between 2nd and 4th group (p�.036) . Mean PFS and OS
were 125days [17-606] and 219days [17-1168] respectively for all 44
patients. Mean PFS and OS of 8 patients with bone metastasis were 75
days and 134 days. Mean PFS and OS of 10 patients with visceral
metastasis were 65 days and 144 days. Mean PFS and OS of 8 patiens with
nodal�visceral metastasis were 154 and 228 days. Mean PFS and OS of
18 patients with nodal metastasis were 166 days and 299 days. Conclusions:
Our longer and multicenter follow-up shows that single agent P in
monotherapy as second, third and fourth line in MUC is associated with
high activity and long-time survival specially in metastatic nodal MUC.
These results suggest that P as monotherapy requires to be further studied,
more patients are being collected.
4586 General Poster Session (Board #3A), Sun, 8:00 AM-12:00 PM
A phase II trial of neoadjuvant dasatinib (Neo-D) in muscle-invasive
urothelial carcinoma of the bladder (miUCB): Hoosier Oncology Group
GU07-122 trial. Presenting Author: Noah M. Hahn, Indiana University
Melvin and Bren Simon Cancer Center, Indianapolis, IN
Background: Neoadjuvant chemotherapy (NC) preceding radical cystectomy
(RC) is an accepted standard for miUCB patients (pts). Dasatinib (D) is an
oral tyrosine kinase inhibitor of Src mediated signaling, and has demonstrated
promising preclinical anti-tumor activity, providing a rationale to
evaluate Neo-D in human miUCB. Methods: A phase II trial was conducted
to assess the safety and biologic activity of Neo-D in miUCB. Key eligibility
criteria included: miUCB (T2-T4a, N0, M0), unsuitable or willing to forego
platinum-based NC, adequate TURBT tissue available, ECOG PS 0-1,
creatinine � 2 x ULN. Pts received D 100 mg po once daily for 28 �/- 7
days followed by RC 8-24 hours after the last dose. The primary endpoint
was feasibility defined as � 60% of pts completing therapy without
treatment-related dose limiting toxicity (DLT) specified as grade 4 hematologic
toxicity, grade 3 non-hematologic toxicity, or any grade 2 toxicity � 14
days. Secondary endpoints included the assessment of biologic activity as
assessed by pre- and post-treatment tumor tissue immunohistochemistry
analysis of Src, pSrc, EPHA2, pEPHA2, FAK, pFAK, AKT, pAKT, CD31,
Ki67, TUNEL. Results: The study completed accrual with enrollment of
25pts. 22 and 24 pts were respectively evaluable for feasibility and toxicity
endpoints. Patient demographics included: median age – 62, M/F – 20/5,
ECOG PS 0/1 – 19/6. Baseline tumor staging included: T2 – 17, T3 – 7.
The study achieved its primary endpoint with 15 pts (68%) completing
therapy without treatment related DLT’s. DLT’s included: fatigue (2 pts),
DVT/PE, abdominal pain, supraventricular tachycardia, enteric fistula, and
hematuria (1 pt each). Frequency of highest observed toxicity on study
included: Grade 1 – 13%, Grade 2 – 38%, Grade 3 – 46%, Grade 4–4%.
Among 22 patients, pathologic stage at RC was T1/Tis in 3 pts (14%), �T2
in 19 pts (86%), and node positive in 6 pts (27%). Correlative analyses of
pre- and post-treatment tumor Src signaling are ongoing and will be
updated at the meeting. Conclusions: Neoadjuvant dasatinib preceding RC
is feasible in miUCB patients. Tumor tissue correlative studies may provide
directions for further development.
4588 General Poster Session (Board #3C), Sun, 8:00 AM-12:00 PM
Clinical validation of the 7th AJCC-TNM nodal staging system in lymph
node-positive patients undergoing radical cystectomy. Presenting Author:
Eila C. Skinner, USC Institute of Urology, University of Southern California,
Los Angeles, CA
Background: The AJCC TNM staging system for bladder cancer has recently
been updated. In the new 7th edition, staging of lymph node (LN)
metastases is based on anatomical location instead of size as in the former
6th edition. This study evaluated whether the prognostic value of nodal
staging according to the 7th edition is superior to the 6th edition. Methods:
Prospectively collected data of patients who underwent radical cystectomy
(RC) at a high-volume center between 2002 and 2008 were reviewed.
Patients who underwent RC for non-urothelial cancer, received neoadjuvant
therapy or had non-LN metastatic disease at the time of RC were
excluded. All patients underwent RC with extended lymphadenectomy up
to the inferior mesenteric artery. LNs were submitted in predesignated
anatomically defined packets. Detailed data on the number, size and
location of LN metastases were recorded. Both the 6th and 7th edition AJCC
TNM editions were used to stage LN positive (LN�) disease. Median
follow-up time was 2.8 years. Kaplan-Meier analysis was used to estimate
overall survival (OS) and recurrence-free survival (RFS). Results: A total of
637 patients were identified of whom 141 patients (22.1%) had LN�
disease. In total, 83 patients (58.9%) received adjuvant chemotherapy.
Administration of adjuvant chemotherapy did not differ significantly per
N-stage according to both editions. Based on the 6th edition, 31 patients
(22.0%) had N1 disease, 105 patients (74.5%) N2 disease and 5 patients
(3.5%) N3 disease. Three-year RFS rates for N1, N2 and N3 disease were
51%, 43% and 0% respectively (p � 0.87). Based on the 7th edition, 29
patients (20.6%) had N1 disease, 60 patients (42.6%) N2 disease and 52
patients (36.9%) N3 disease. Three-year RFS rates for N1, N2 and N3
disease were 51%, 42% and 45%, respectively (p � 0.84). Conclusions:
Neither the AJCC-TNM 7th edition (location-based) LN staging nor the 6th edition (size-based) staging performed well as a prognostic tool for the
patients in this cohort. The new staging system moved a large percent of
patients into the N3 category, which did not have a worse prognosis than
either the N1 or N2 categories. A better staging system for LN� bladder
cancer patients needs to be developed.
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