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

Lung Cancer—Non-small Cell Local-Regional/Small Cell/Other Thoracic Cancers
7096 General Poster Session (Board #41G), Sat, 1:15 PM-5:15 PM
Investigation of PARP1 as a therapeutic target in small cell lung cancer.
Presenting Author: Lauren Averett Byers, University of Texas M. D.
Anderson Cancer Center, Houston, TX
Background: Small cell lung cancer (SCLC) is an aggressive malignancy that
differs from non-small cell lung cancer (NSCLC) in its metastatic potential
and response to treatment. To date, no molecularly-targeted agent has
prolonged survival of SCLC patients. Using a proteomic approach, we
previously identified high expression of the DNA repair protein poly
(ADP-ribose) polymerase 1 (PARP1) in SCLC cell lines and tumors. Here we
test in vitro sensitivity of SCLC to PARP inhibition or knockdown. Methods:
Cell lines were treated with PARP inhibitor olaparib or AG014699 for 14d
�/- chemotherapy. Relative cell viability was assessed by cell count. siRNA
against PARP1 was compared with scrambled siRNA and mock transfected
cells. To assess DNA repair, RAD51 foci were counted after 1�M or5�M
olaparib and after 8Gy irradiation (RT). Results: SCLC cell lines were highly
sensitive to PARP inhibition by olaparib (IC50s �0.5 �M for H69; �2�M
in H524, H82, and H526) and AG014699 (IC50s �0.5 �M for H82, H69,
and H524; 2.2 �M for H526 and H841). In contrast, A549 (NSCLC) was
resistant to both drugs (IC50s �8�M). Because BRCA1/2 and PTEN
mutations are associated with greater sensitivity to PARP inhibitors, we
compared SCLC sensitivity with that of BRCA1-mutated (HCC1395) and
PTEN-mutated (MDA-MB-468) breast lines. As expected, HCC1395 and
MDA-MB-468 were sensitive to both PARP inhibitors. Remarkably, however,
SCLC cell lines were as sensitive or more so. Combination of olaparib
with topotecan or irinotecan (commonly used in SCLC) decreased tumor
cell viability more than either agent alone (p �0.03). Consistent with the
drug studies, knockdown of PARP1 by siRNA decreased growth of SCLC
compared with that of controls. RAD51 foci increased in SCLC after
olaparib treatment (�4-fold) and RT (�18-fold). Conclusions: SCLC lines
were as sensitive to PARP inhibition as BRCA1- or PTEN-mutated breast
cancer lines. Moreover, PARP inhibition enhanced the effect of chemotherapy
on SCLC lines. Increased formation of RAD51 foci in SCLC cells
after olaparib or RT suggests a deficiency in homologous recombination
that may account for the sensitivity to PARP inhibitors. These results
support the investigation of PARP inhibition as a novel therapeutic
approach in SCLC lung cancer.
7098 General Poster Session (Board #42A), Sat, 1:15 PM-5:15 PM
Impact of PET staging in limited-stage SCLC. Presenting Author: Eric
Xanthopoulos, Department of Radiation Oncology, University of Pennsylvania
School of Medicine, Philadelphia, PA
Background: Although PET/CT has been established for the initial staging of
NSCLC, it is still unproven for SCLC. This study examines clinical outcome
in patients with limited-stage SCLC staged with and without PET/CT.
Methods: An institutional database was reviewed to identify all patients that
presented with limited-stage SCLC and treated definitively with concurrent
chemoradiation. Overall survival and associations were assessed by the
Kaplan-Meier approach, log-rank tests and Cox modeling. Results: From
01/04 – 08/10, 54 consecutive limited-stage SCLC patients were treated
with concurrent chemoradiation at the University of Pennsylvania. 40
patients underwent PET staging; 14 underwent CT staging only; all had MR
of the brain. Patient characteristics were well distributed, including age (p
� 0.35), race (p � 0.21), sex (p � 0.93), dose (45 Gy, p � 0.89), and
fractions per day (p � 0.89). PET-staged patients had median survival of
32 vs 15 months in patients without PET (p � 0.03). Survival rate was
57% vs 29% at 24 months. Median time to distant failure of 29 vs 11
months (p � 0.05). Median time to local failure was 41 vs 12 months (p �
0.03). Median followup was 38 months in the 19 surviving PET-staged
patients and 40 in the 2 surviving non-PET patients (p � 0.59). Lack of
PET-staging (OR � 0.92, p � 0.04) and race (OR � 1.02, p � 0.03)
associated with increased distant failure on multivariate Cox analysis. Only
PET-staging (OR � 0.93, p � 0.04) associated with increased overall
survival on univariable Cox modeling. Conclusions: Median and overall
survival of PET-staged SCLC patients compared favorably with those who
were not. These findings are presumably due primarily to identification of
CT-occult distant disease by PET. This study underscores the value of PET
in staging patients with SCLC.
475s
7097 General Poster Session (Board #41H), Sat, 1:15 PM-5:15 PM
Expression pattern and biologic relevance of Bcl-2 and Mcl-1 in pulmonary
neuroendocrine tumors. Presenting Author: Rajasree Pia Chowdry, Emory
University, Atlanta, GA
Background: Bcl-2 protein overexpression is frequently described in small
cell lung cancer (SCLC) but the biological relevance remains unclear. To
better elucidate the role of Bcl2 dysfunction in SCLC, we assessed the total
and the biologically relevant phosphorylated forms of the anti-apoptotic
Bcl2 family members (Bcl2, pBcl-2, Mcl-1, pMcl-1) in pulmonary neuroendocrine
(NE) tumors. Methods: We analyzed archival samples of pulmonary
carcinoid, SCLC and large-cell NE carcinoma (LCNEC) by immunohistochemistry
(IHC) using specific antibodies. Protein expression was assessed
by light microscopy using standard scoring of intensity (0, 1, 2 and 3) and
percent cell staining and correlated with age, gender, smoking status,
tumor type, stage and survival. Significant differences in expression pattern
and correlation with clinical variables were assessed by Wilcoxon twosample
test, t-test, ANOVA, Spearman and Pearson correlation coefficients
and Cox regression model. Results: We retrieved 77 cases: carcinoid (16)
SCLC (41) and LCNEC (20); median age (61 yrs), gender (62% females).
Bcl2 and pBcl2 expression was higher in SCLC and LCNEC compared to
benign carcinoid tumor. pBcl-2 showed stronger correlation with adverse
features including smoking, malignant histology, higher stage at diagnosis
and worse survival. No significant association of Mcl1 or pMcl-1 expression
with clinical or pathologic parameters. Conclusions: pBcl-2 expression
pattern and correlation with adverse prognostic features indicate a key role
in SCLC biology and relevance as a therapeutic target.
Biomarker Carcinoid SCLC LCNEC P value
Cytoplasmic Bcl-2 7 97 124 0.0005
Cytoplasmic pBcl-2 42 132 83 0.0007
Cytoplasmic Mcl-1 230 232 253 0.5327
Cytoplasmic pMcl-1
Correlation of biomarkers and OS
131 173 165 02919
HR (95% CI)
Cytoplasmic Bcl-2 1.01 (1.00-1.02) 0.0167
Cytoplasmic pBcl-2 1.57 (1.09-2.26) 0.0165
Cytoplasmic Mcl-1 1.12 (0.73-1.70) 0.6131
Cytoplasmic pMcl-1
Correlation of biomarkers and PFS
0.96 (0.67-1.40) 0.8462
HR (95% CI)
Cytoplasmic Bcl-2 1.01 (1.00-1.02) 0.0072
Cytoplasmic pBcl-2 1.39 (1.02-1.89) 0.0383
Cytoplasmic Mcl-1 1.19 (0.82-1.73) 0.3531
Cytoplasmic p-Mcl1 1.00 (1.00-1.01) 0.0402
7099 General Poster Session (Board #42B), Sat, 1:15 PM-5:15 PM
A phase II trial of pazopanib in relapsed/refractory small cell lung cancer
(SCLC). Presenting Author: Leena Gandhi, Dana-Farber Cancer Institute,
Boston, MA
Background: Despite response to initial therapy, SCLC has high rates of
relapse or distant metastasis and limited 2nd-line therapeutic options.
Angiogenesis is an essential part of cell invasion, dissemination, and
outgrowth of distant metastases and therefore is a potential therapeutic
target in SCLC. Pazopanib (Votrient, GSK) is a potent, competitive inhibitor
of the tyrosine kinase activity of VEGFR-1, VEGFR-2, VEGFR-3, PDGF, and
c-kit. We initiated a phase II single-arm trial of pazopanib in relapsed or
refractory SCLC to determine impact on disease progression. Methods:
Patients were eligible if they had progressive disease following up to two
lines of prior therapy. Patients were treated at the FDA-approved dose of
800 mg pazopanib once daily. The primary endpoint was progression-free
rate (PFR) at 8 weeks. Secondary endpoints included median progressionfree
survival, overall survival, and safety. The trial followed a Simon 2-stage
design to limit accrual if no therapeutic benefit was observed. Results: To
date, 27 of 30 planned subjects have been enrolled since October 2010.
Two did not complete cycle 1 and were considered inevaluable for
response. Major toxicities (mostly grade 1/2) were those previously described
including nausea, fatigue, hypertension, electrolyte abnormalities,
and AST/ALT elevations (grade 3 in 4 subjects). Three subjects were
removed from study due to toxicity: 1 with grade 3 nausea, 1 with grade 3
drop in the cardiac ejection fraction, and 1 with multiple grade 2 toxicities
including diarrhea, fatigue, and nausea. A fourth was removed due to grade
1 hemoptysis despite clinical response. The PFR at 8 weeks of 21 subjects
evaluable for response to date was 52%; 4 of these 11 subjects had
chemo-refractory disease. There were no confirmed responses, but tumor
regressions ranged from 2-20%. Median progression-free survival is 14.1
weeks. Conclusions: In patients with SCLC, single-agent pazopanib demonstrated
a notable rate of stable disease (including among chemo-refractory
patients) and a median PFS that exceeds that of historical PFS rates of � 2
months on ineffective 2nd-line therapies. These data suggest that the
potential for pazopanib in SCLC treatment should be further investigated.
Visit abstract.asco.org and search by abstract for the full list of abstract authors and their disclosure information.