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

4589 General Poster Session (Board #3D), Sun, 8:00 AM-12:00 PM
Mortality from other malignancies in bladder cancer survivors. Presenting
Author: Hamed Ahmadi, USC Institute of Urology, University of Southern
California, Los Angeles, CA
Background: Other-cause mortality represents a considerable proportion of
overall long-term mortality in bladder cancer (BC) patients who underwent
curative radical cystectomy (RC). Other malignancies besides BC are
reportedly among the most common etiologies of other-cause mortality. We
report on mortality from other malignancies in BC survivors who have
undergone prior RC. Methods: Data on BC patients who died of other
malignancies were derived from a cohort of 1964 patients with pathologic
diagnosis of urothelial carcinoma of bladder who underwent RC with intent
to cure due to BC at University of Southern California between 1971 and
2008. For subsequently developed malignancies, the time interval between
RC and occurrence of malignancy was calculated. Other malignancies
mortality was evaluated with respect to gender, pathological stage of
BC, and type of malignancy. Results: Other malignancies were diagnosed in
463 (23.5%) patients. They were the cause of death in 122 (6.21%)
patients (109 male) who had a median age of 68.6 (range 43.4 – 88.7) at
time of RC. Of all 122 patients with other malignancies, 22(18%) patients
were diagnosed prior to RC, 5 (4%) concurrently with BC diagnosis, and 94
(77%) subsequent to RC. At the time of cystectomy, 87/122 (71.3%)
patients had lymph node-negative organ-confined disease, compared to
56.3% in the whole cohort; and 18 (14.7%) patients had nodal disease,
compared to 23.2% in the whole cohort. 116/122 (95%) of these patients
had no evidence of BC recurrence at time of death. Secondary cancers
occurred at a median of 7.7 years (Range 3 months – 29.9 years) after RC.
Most common sites and types of malignancies that led to death were lung in
43/122 (35.2%), predominantly non-small cell carcinoma in 17/
43(39.5%); hematologic in 15/122 (12.3%), largely lymphoma in 6/15
(40%); and colon in 11/122 (9%), primarily adenocarcinoma in 8/11
(72.7%) patients. Conclusions: Lung, hematologic, and colon cancers are
the most common causes of death due to other malignancies in BC
survivors and more commonly found in male patients with lymph nodenegative
organ-confined tumor. Continued screening for other cancers in
the follow-up of BC survivors may be warranted.
4591 General Poster Session (Board #3F), Sun, 8:00 AM-12:00 PM
Novel oncogenic function of ATDC in bladder cancer. Presenting Author:
Phillip Lee Palmbos, University of Michigan Health System, Ann Arbor, MI
Background: Bladder cancer is a common and deadly disease, but the
molecular events leading to its initiation and progression are incompletely
understood. We recently identified Ataxia-Telangiectasia Group D Associated
(ATDC) as a novel oncogene which drives tumor proliferation and
invasion in pancreatic carcinoma (Cancer Cell, 2009). In this study, we
describe the role of ATDC as an oncogene in bladder cancer. Methods: To
further determine the oncogenic role of ATDC, we generated ATDC
transgenic (tg) mice in which ATDC expression was driven by a CMV
promoter and characterized the resulting tumors. Results: Interestingly, the
dominant phenotype in these mice was the development of both noninvasive
and invasive urothelial carcinomas (9% and 20% respectively,
average age of onset 10-12 months of age). Histologically, these tumors
were indistinguishable from human urothelial carcinomas. Gene expression
profiling of invasive tumors derived from ATDC tg mice demonstrated a
marked overlap with gene signatures of human invasive bladder cancers.
ATDC was the 11th most highly up-regulated gene in bladder cancers
represented in the Oncomine gene expression database. Analysis of a
human bladder cancer tissue microarray (311 samples) by IHC showed
elevated expression in 70% (173/252) of muscle-invasive carcinomas,
22% (5/23) of papillary tumors and little or no expression in normal
bladder urothelium. ATDC tg mouse bladder tumors demonstrated loss of
p53 signaling and down-regulation of PTEN expression, which correlated
with ATDC induced methylation of the PTEN promoter by DNMT3A.
Furthermore, ATDC knock-down in invasive cancer cell lines resulted in
decreased proliferation, invasion and reactivation of p53-mediated signaling
and PTEN expression. Conclusions: ATDC is a novel oncogene that is
highly expressed in human bladder cancers and is sufficient to drive the
development of invasive bladder tumors in tg mice. The mechanism by
which ATDC drives bladder cancer formation involves alterations in p53
and PTEN pathways known to be important in bladder tumorigenesis.
Genitourinary Cancer
299s
4590 General Poster Session (Board #3E), Sun, 8:00 AM-12:00 PM
Second-line treatment of advanced urothelial cancer with paclitaxel and
RAD001 (everolimus) in a German phase II trial (AUO trial AB 35/09).
Presenting Author: Guenter Niegisch, Department of Urology, Heinrich-
Heine-University, Duesseldorf, Germany
Background: Efficacy of second-line treatment after cisplatinum failure in
patients (pts) with advanced urothelial cancer is limited. Based on
encouraging preclinical data and results from several phase I trials in solid
cancers, we evaluated the safety and efficacy of the combination of
paclitaxel and RAD001 (everolimus) in these pts. Methods: In this singlearm,
multicenter phase II trial, pts failing prior cisplatinum based combination
treatment for advanced urothelial cancer were treated with paclitaxel
(175 mg/m² i.v., three-weekly) and the mTOR-inhibitor RAD001 (10 mg
p.o., once daily). Pts were treated until tumor progression by RECIST
criteria or until a maximum of 6 cycles was completed. A one-stage design
was used to evaluate the overall response rate (ORR) as primary endpoint.
Results: 27 pts (18 men, 9 women; median age 63 (35-76) years; ECOG �
1: 11/27pts, hepatic metastases: 10 pts, Hb�10 g/dl: 8 pts; upper urinary
tract: 9 pts, lower urinary tract 15 pts, both: 3 pts) were enrolled between
07/09 and 12/11. As of 01/12, 19 pts are evaluable for the primary
endpoint and the toxicity profile (6 pts still on treatment, 1 patient has
withdrawn consent). Main toxicities (all CTCAE grades) were anemia
(10/19 pts), leucopenia (8/19 pts), and neuropathy (9/19 pts). Grade III/IV
toxicities were anemia (4/19 pts) and leucopenia (4/19 pts). No treatment
related deaths were observed. Median number of cycles was 4 (1-6).
Complete remission (CR) and partial remission (PR) was observed in 0/19
and 3/19 pts, respectively (ORR 16%). Stable disease (SD) was observed in
10/19 pts. Median time-to-progression (TTP) was 2.7 months (95%
confidence interval [CI] 1.6 – 4.4), median overall survival (OS) was 6.5 (CI
4.5 – 9.2) months. Conclusions: Frequency and severity of toxicities were
acceptable. Using the combination of RAD001 and paclitaxel as secondline
treatment for advanced urothelial cancer after cisplatinum-failure,
response rates and survival times comparable to vinflunine were observed.
4592 General Poster Session (Board #3G), Sun, 8:00 AM-12:00 PM
External validation of prognostic models for overall survival (OS) in patients
(pts) with advanced cancer (UC) treated with cisplatin-based chemotherapy.
Presenting Author: Andrea Borghese Apolo, Medical Oncology
Branch, National Cancer Institute, National Institutes of Health, Bethesda,
MD
Background: The most commonly used model predicting OS for UC pts
treated with cisplatin-based chemotherapy is based on 2-variables (visceral
metastases and performance status), developed at MSKCC in 1999, and
validated in a phase III study (DeSantis JCO 2011). A prognostic model of
OS for advanced UC pts based on 4 variables (visceral metastases,
albumin, performance status, and hemoglobin) was developed using 308
pts from MSKCC (ASCO 2007 abstr 5055). We report the discriminative
ability of the 4- and 2- variable models for advanced UC pts using an
independent dataset from CALGB 90102. Methods: The analysis was
performed using an external multi-institutional dataset from CALGB
90102. The primary measurement of predictive discrimination was Harrell’s
c-index which was computed with 95% confidence interval (CI). To
assess whether there was a statistically significant difference in discrimination
between the two models, the U statistic was used to test whether the
predictions of the 4-variable model in all possible pairs were more
concordant with actual observations than the 2-variable model in the same
pairs. Results: CALGB 90102 included 74 UC pts (58 males, 16 females),
median age 64 years, treated with cisplatin, gemcitabine and gefitinib,
enrolled from 7/02 to 4/05 with a median follow-up of 72.5 months.
Visceral metastases were present in 64% (bone, 18%, liver, 31%, lung,
43%), median KPS 90%. The MSKCC 2-variable risk group distribution
was 30% �0, 65%� 1 and 5%�2. The median OS �12.7 months (95%
CI�10.4-20.5) with 68 deaths observed. When applied to the CALGB
cohort, the predictive accuracy for the 4- and 2-variable models were 0.63
(95 CI� 0.56- 0.69) and 0.58 (95% CI� 0.52-0.65), respectively. There
was a statistically significant difference in discrimination between the two
models (p �0.019), with superiority of the 4-variable model compared to
the 2-variable model. Conclusions: A 4-variable prognostic nomogram for
survival in pts with advanced UC was superior to a 2-variable risk-group
model. The 4-variable prognostic model may replace the widely used
2-variable model and can be used in the design and conduct of future
phase II and III trials in advanced UC.
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