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

4581^ General Poster Session (Board #2C), Sun, 8:00 AM-12:00 PM
Phase II trial of neoadjuvant gemcitabine (G) and cisplatin (C) with
sunitinib in patients (pts) with muscle-invasive bladder cancer (MIBC).
Presenting Author: Arjun Vasant Balar, Memorial Sloan-Kettering Cancer
Center, New York, NY
Background: Response to neoadjuvant chemotherapy (NC) prior to radical
cystectomy (RC) predicts improved overall survival (OS) in MIBC. Associations
with enhanced survival include complete pathologic response (pT0;
Grossman, NEJM 2003) and eradication of the muscle-invasive component
(�pT2; Splinter, J Urol 1992). Sunitinib (S) is active in pretreated pts with
advanced disease. We tested if S added to GC was safe, improved the rate
of pT0, and improved the rate of �pT2. Methods: Cisplatin-eligible pts with
cT2-4aN0 bladder cancer received G 1000 mg/m2 and C 35 mg/m2 on day
(D) 1 and D8 with S 25 mg orally daily D1-14 of a 21D cycle for 4 cycles.
RC plus pelvic lymph node dissection was required to assess response of
pT0 or �pT2. A Simon’s Minimax 2-stage design was used to test a null
(H0) pT0 rate � 20% against alternative (H1) pT0 rate � 40% with Type I
and II error rates of 0.05 and 0.10 respectively. Enrollment to the 2nd stage
of 45 patients was planned if � 6 of the initial 24 evaluable pts achieved
pT0. Primary endpoint was pT0N0 and secondary endpoints were: response
defined as �pT2N0; safety; time to progression (TTP), and OS.
Results: 18 pts (15M, 3F), median age 63 (54-76) were enrolled from 6/09
and 10/11 after which financial support was withdrawn. 3 pts were
inevaluable for response endpoints due to: 1.) withdrawal of consent, 2.)
declining any surgery, 3.) partial cystectomy instead of RC. All 18 were
evaluable for safety, TTP and OS. 1 of 15 pts had pT0N0 (6.6%; 95% CI
0.34 – 29.8%) and 5 had �pT2N0 (33%; 95% CI 15-58%). 4 of 5 pts
with status �pT2N0 were pTisN0. Median TTP was 10 months (95% CI
3.5-NR). 3 pts were deceased at time of analysis; median OS not reached.
Neutropenia due to the 3 drug combination required routine GCSF support
on day 8 of each cycle. Grade 3/4 toxicities were anemia (11 pts),
neutropenia (6), thromboembolic events (2), febrile neutropenia (2) and
infection (2). Conclusions: Despite incomplete accrual, the pT0 rate was
low suggesting that S does not add to GC. Residual non-invasive disease
(�pT2) was common, including a large proportion of pts with pTisN0.
Given these findings, response criteria for future NC studies should
consider either �pT2 or � pTis as the primary endpoint.
ABSTRACT
WITHDRAWN
Genitourinary Cancer
297s
4582 General Poster Session (Board #2D), Sun, 8:00 AM-12:00 PM
PI3KCA mutations in advanced urothelial carcinoma: A potential therapeutic
target? Presenting Author: Joaquim Bellmunt, University Hospital del
Mar-IMIM, Barcelona, Spain
Background: PI3KCA is frequently mutated in human cancer; however,
information is scarce regarding its relevance in urothelial carcinoma (UC).
We determined the prevalence of mutation and impact on clinical outcome
of PI3KCA uniformly-treated patients with metastatic UC. Impact of PI3K
and dual PI3K/mTOR inhibition was tested in vitro in UC cell lines with
either H1047R or E545K mutation. Methods: 141 samples from invasive
UC were scanned for mutations. Of those, complete clinical data was
available from 85 cases treated with platinum-based combination chemotherapy
for advanced or metastatic disease. DNA was extracted from FFPE
material. Mutation status was determined by iPLEX sequencing and
confirmed with hME sequencing. Overall survival (OS) was measured from
beginning of treatment for metastatic disease to time of death or censored
on the last known alive date. Cox proportional hazard model was used to
assess the associations of PI3K mutational status and OS. Growth
inhibitory effects of a specific PI3K inhibitor and a dual PI3K/mTOR
inhibitor (both from Selleck) on UC cell lines with or without mutations
were tested using MTT assays. Results: Mutations in the PI3KCA gene were
observed in 14 (10%; 95% CI 6-16%) specimens. E545K was detected in
all 14 specimens, though one specimen contained mutation at both E545K
and H1047R. Among patients with clinical data, there was no statistically
significant association between PI3KCA mutational status and OS (HR for
having PI3KCA�0.49, 95% CI [0.15, 1.57], p-value 0.22). Preliminary in
vitro experiments showed that cell growth was more potently inhibited with
dual PI3K/mTOR inhibitors than with PI3K inhibitors. Conclusions: Mutations
in the PI3KCA gene were detected in 10% of invasive UC and did not
correlate with OS in patients with metastatic UC treated with platinumbased
chemotherapy. PI3K inhibition in vitro impacts UC cell growth,
though dual PI3K/mTOR inhibitors may have more significant effects than
PI3K inhibition alone.
4584 General Poster Session (Board #2F), Sun, 8:00 AM-12:00 PM
PIK3CA gene alterations in bladder cancer: Analysis of correlative series of
transurethral resection (TUR)—Correlation with grade histology and tumor
size. Presenting Author: Daniel E. Castellano, University Hospital 12 de
Octubre, Madrid, Spain
Background: PI3K pathway involvement in bladder cancer is well documented
and activating mutations of the gene have been identified,
particularly in tumors of low grade and stage. We have analyzed hot spot
mutations and copy number in PIK3CA gene as well as mRNA expression
levels in tumor tissue of pts with urothelial cell carcinoma (UCC). Methods:
90 pts were analyzed. In 85 pts, fresh tissue from tumor and adjacent
normal tissue was collected. All pts signed an informed consent and basic
demoghrapics data were collected. Histology confirmation of UCC was
required. PIK3CA alterations were analyzed by quantative-PCR. Results:
Patient«s characteristics were: median age 73 years, Ta 45.5%, T1
41.1%, T2 12.2%; high-grade histology 43.4%, low-grade 51,1%, PULMP
4,4%. With a median follow-up of 10.0 months, 21% tumor recurrences
were observed. 13% normal tissue and 51,8% tumor samples harbored
alterations in PIK3CA gene, including alterations affecting the helical
domain (mutations 65%, amplifications 60%, both 21%). According to T
stage the distribution was: 10/36 Ta, 26/35 T1 y 6/10 T2. (p�0.05). When
analyzing factors related to tumor recurrence, it was found that PIK3CA
gene mutations in E542 or E545 had a lower recurrence risk (p-value
²0.045). Differential expression analysis (genome-wide transcriptome analysis/microarray)
showed that tumors bearing altered PIK3CA gene are more
similar to non-tumoral samples comparing with tumors bearing wtPIK3CA
gene. Moreover, overexpressed genes in mutant samples are mainly
involved in G-protein and Wnt signaling, whereas underexpressed genes are
involved in cell morphogenesis and cell polarity. Conclusions: We observed
that PIK3CA gene alterations is an early carcinogenesis event in UCC pts,
and more frequently found in larger tumor stages. These data support that
PIK3CA status may constitute a good prognostic tool, as well as a
therapeutic target in stratified groups for bladder cancer.
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