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

Lung Cancer—Non-small Cell Local-Regional/Small Cell/Other Thoracic Cancers
7022 Poster Discussion Session (Board #14), Sun, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Vorinostat (V) intratumoral levels and biomarker response in a window of
opportunity trial in patients with resectable aerodigestive tract cancer.
Presenting Author: Konstantin H. Dragnev, Dartmouth-Hitchcock Medical
Center, Lebanon, NH
Background: Aerodigestive tract cancer (ADT) is the leading cause of
cancer-related death in the US. New effective treatments are needed.
Among a panel of drugs causing growth inhibition of lung cancer cells and
repression of cyclin D1, the histone deacetylase inhibitor V was found most
potent. To translate studies into the clinic, a window of opportunity trial of V
was conducted. Methods: Pts with resectable ADT received 400 mg V once
daily orally for 7 days prior to surgical resection. Serum samples were
obtained before the last V dose and at the time of biopsy. Tumor tissue was
immediately snap-frozen in liquid nitrogen, stored at -70°C, homogenized
in three parts PBS (1:3g/v). V was quantitated with a LC-MS/MS assay.
Post- versus pre-treatment tumor biopsies were scored for necrosis, acute
and chronic inflammation, and immunohistochemical changes in Ki-67,
cyclin E, cyclin D1, EGFR, phospho-EGFR, p21, p27 and caspase. Results:
15 pts enrolled, 9 pts took V for a median of 7 days (3-9), underwent
resection and had adequate pretreatment samples. Median age 66, 4
women, 4 former, 5 current smokers, 1 squamous cell lung carcinoma, 8
adenocarcinoma (1 esophageal). PK analyses confirmed plasma (8pts) and
tumor (7pts) concentrations above the detection limits. There was considerable
interindividual variation in plasma V concentrations (7.3-192.4
ng/ml; CV 95%), at 178-500 min from last V dose, and in intratumoral V
levels (15.0-80.3 ng/g; CV 59%). All pts had wild-type EGFR, 4 pts had
KRAS codon 12 mutations, 78% showed reduced Ki-67 expression, 50%
had decreased cyclin E, 78% exhibited necrosis, chronic or acute inflammation
in the post-treatment biopsies. Most cases with KRAS mutations
had biomarker responses. Changes in multiple biomarkers were observed
across the range of intratumoral V levels. Conclusions: This is the first report
of V concentrations in human tumors. Preoperative treatment with V
achieved intratumoral concentrations comparable to serum with evidence
of necrosis, decreased Ki-67 and cyclin E, and other biomarker responses
in resected ADT. The results demonstrate the value of window of opportunity
trials in the investigation of novel cancer therapeutics.
7024 Poster Discussion Session (Board #16), Sun, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Predictors of survival after resections of synchronous lung cancers located
in mutiple lobes: A multi-institutional pooled analysis. Presenting Author:
Tawee Tanvetyanon, H. Lee Moffitt Cancer Center & Research Institute,
Tampa, FL
Background: Surgical resection is a treatment option for patients with
multiple primary lung cancers. However, for synchronous disease, it is
often difficult to differentiate this condition from metastatic disease,
especially when cancers are distributed in multiple lobes or in both lungs.
Some people believe that surgery should be avoided when patients have
bilateral cancers or when all cancers have the same histology. To date,
however, available evidences are limited by small sample size. Methods:
Studies (published 2008-2011) of curative resection for patients with
synchronous (� 2-year interval) multiple lung cancers located in � 2 lobes,
but without radiographic evidence of distant metastasis, were identified
from literature. Corresponding authors were contacted and individual
patient data were obtained. Patients with multiple cancers, but localized
only to one lobe, were not included. Databases were pooled and multivariable
Cox Proportional Hazard models were fit to adjust for confounders.
Results: There were 467 patients included from 6 studies. Median overall
survival was 52.0 months (95% CI: 45.6-63.7). Postoperative (30-day)
mortality rate was 1.9%. In a multivariable model, study site or having
pneumonectomy did not independently impact on survival. However, age,
gender, nodal stage, tumor location, and histological similarity were
independent predictors of survival. Advanced age increased mortality
(p�0.012). Male sex increased mortality compared with female: HR 1.64
(95% CI: 1.23-2.19, p�0.0008). N2 or N1 increased mortality over N0:
HR 1.85 (95% CI 1.29-2.66, p�0.0008) and 1.97 (1.43-2.73,
p�0.0001), respectively. Unilateral location increased mortality over
bilateral location: HR 1.62 (95% CI 1.23-2.13, p�0.0002). Different
histology increased mortality over similar histology: HR 1.45 (95% CI
1.11-1.90, p�0.0069). Conclusions: In this largest multi-institutional
database of resected multiple lung cancers of multiple lobes to date, we
found no evidence of inferior survival among patients having bilateral
cancers or having all cancers with the same histology. In fact, the survival
among such patients appears superior to their counterparts.
7023 Poster Discussion Session (Board #15), Sun, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Use of a proliferation-based mRNA signature to predict outcome in
early-stage non-small cell lung adenocarcinoma. Presenting Author: Carmen
Behrens, University of Texas M. D. Anderson Cancer Center, Houston,
TX
Background: Adjuvant treatment of patients with early-stage lung adenocarcinoma
is based on post-surgical pathological staging and patient performance
status. Disparate outcomes within each staging group suggest that
additional prognostic markers could improve our understanding of riskbenefit
and potentially lead to better treatment decisions. A proliferationbased,
mRNA expression profile was applied to public microarray data of
surgically treated lung adenocarcinomas and a cohort of FFPE samples to
test its potential prognostic utility. Methods: Public expression data
(Director’s Consortium, DC) were derived from Affymetrix HG-U133A
arrays. Clinical FFPE samples were assayed by quantitative PCR. A cell
cycle progression (CCP) score was calculated from the expression average
of 31 cell cycle genes normalized by 15 housekeeper genes. The prognostic
value of the CCP score to predict stage I and II patient outcomes was
evaluated by Cox proportional hazards analysis with disease-related death
as the primary outcome measure. Results: In 256 DC cases, the CCP score
was a significant predictor of death in univariate (p�0.0001) and multivariate
analysis (p�0.001, HR 1.57, 95%CI 1.20-2.05) using age, stage,
gender, smoking status and treatment as covariates. Similarly, in a second
data set (GSE31210, n�204) the CCP score was highly associated with
death (univariate, p�0.001; multivariate analysis, p�0.003, HR 1.81,
95% CI 1.24-2.66). Using quantitative PCR, the signature was applied to
381 FFPE samples with a median follow-up of 5 years collected at the MD
Anderson Cancer Center and the European Institute for Oncology. In the
presence of clinical covariates (as above and tumor size and pleural
invasion), the CCP score remained the most significant predictor of death in
univariate (p�0.0003) and multivariate analysis (p�0.007, HR 1.50,
95% CI 1.11-2.02). Conclusions: A 46 gene mRNA signature is a
significant predictor of disease-related death in early-stage lung adenocarcinoma,
providing independent prognostic value in the presence of clinical
variables. This molecular predictor of cancer survival will be studied in
additional cohorts for its ability to impact clinical treatment decisions.
7025 Poster Discussion Session (Board #17), Sun, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Prognostic impact of the number of examined lymph nodes (LNs) in
resected node negative (pNo) non-small cell lung cancer (NSCLC). Presenting
Author: Obiageli Uchenna Ogbata, University of Tennessee Health
Science Center, Memphis, TN
Background: In the US, 29% of patients undergo curative-intent surgery for
NSCLC. Absence of LN metastasis and the extent of LN examination
influence survival. 44% of patients with pathological node negative (pN0)
disease die within 5 years. There is no consensus on the optimal number of
LNs to be examined to determine pN0 stage. We hypothesized that patients
with few examined nodes may have missed nodal metastasis and increasing
the number of LNs examined would improve survival. Methods: Retrospective
SEER database analysis of NSCLC resections from 1998 to 2002, with
survival updated to 2008. Patients with first primary, pN0 NSCLC, with one
or more LNs examined, met our study criteria. Cox regression and
competing risk models were used for survival analysis. A p value �0.05 was
considered statistically significant. Results: 8,137 patients met inclusion
criteria and were evaluated. A median of 6 LNs were examined in this
cohort. Patients who underwent pneumonectomy and lobectomy had more
LNs examined than those who had sub-lobar resections. Higher number of
LNs examined was associated with better overall survival (OS) and lung
cancer specific survival (LCSS), at a plateau of 8 LNs for both outcomes
(Table). Having mediastinal LNs examined also resulted in increased OS
and LCSS (p�0.05). Conclusions: The pathologic assessment of LNs in
surgical specimens is often suboptimal. Examining more LNs may have
increased the likelihood of correct staging. Lower numbers of LNs examined
probably result in understaging. Examining 8 or more total LNs and
mediastinal LNs examined improved both OS and LCSS.
#ofLN
examined
Hazard
ratio
for OS
P value
for OS
95% CI
for OS
Hazard
ratio
for LCSS
P value
for LCSS
457s
95% CI
for LCSS
2 0.97 0.652 0.85 – 1.11 0.88 0.138 0.74 – 1.04
3 0.93 0.262 0.81 – 1.06 0.87 0.101 0.74 – 1.02
4 0.94 0.342 0.82 – 1.07 0.82 0.026 0.69 – 0.98
5 0.83 0.008 0.72 – 0.95 0.78 0.008 0.66 – 0.94
6 0.82 0.008 0.71 – 0.95 0.77 0.004 0.64 – 0.92
7 0.86 0.052 0.74 – 1.00 0.76 0.005 0.62 – 0.92
8 0.78 0.003 0.66 – 0.92 0.71 0.002 0.58 – 0.88
9 0.85 0.052 0.73 – 1.00 0.79 0.026 0.64 – 0.97
10 0.81 0.022 0.68 – 0.86 0.75 0.016 0.60 – 0.95
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