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Annals of Oncology
were randomly selected from the Tayside (n = 224) and Cuneo (n = 150) Tissue
Banks. Tissue samples were subject to histopathological review to ensure adequate
representation of cancer cells.
Results: Although ASS1 or ASL methylation could not be verified in breast cancer cell
lines, ASS1 methylation was evident in a significant proportion of primary or metastatic
breast cancer samples. In two independent series, aberrant methylation of ASS1 was
detected in 4.5% and 16% of primary breast cancers. The incidence was even higher in
metastatic breast cancer, with 47% of resected brain metastases (n = 19) showing
methylation of ASS1 and 26% showing additional methylation of ASL, a combination
that has shown to be highly sensitive to ADT. ASS1 methylation status as called by MSP
agreed with that determined by pyrosequencing in all cases assessed by both methods.
No significant association with a specific tumour type or outcome was found.
Conclusions: A significant proportion of primary and metastatic breast cancers show
methylation-dependent transcriptional silencing of ASS1 or ASL and might be
candidates for arginine depletion therapy.
Disclosure: All authors have declared no conflicts of interest.
1661P THE PREDICTIVE ROLE OF THE 53BP1 PATHWAY IN
ADVANCED NON-SMALL-CELL LUNG CANCER (NSCLC)
PATIENTS (P) TREATED WITH FIRST-LINE
PLATINUM-BASED CHEMOTHERAPY
L. Bonanno 1 , C. Costa 2 , M. Majem 3 , A. Gimenez-Capitan 2 , I. Rodriguez 4 ,J.
J. Sánchez 5 , B. Massuti Sureda 6 , A. Favaretto 1 , M. Rugge 7 , R. Rosell 8
1 U.o.Oncologia Medica, Istituto Oncologico Veneto IOV-IRCCS, Padova, ITALY,
2 Laboratoy of Biology Department, Pangaea Biotech, USP Dexeus University
Institute, Barcelona, SPAIN, 3 Oncology, Hospital de Sant Pau, Barcelona,
SPAIN, 4 Statistics, USP Dexeus University Institute, Barcelona, SPAIN,
5 Statistics, Autonomous University of Madrid, Madrid, SPAIN, 6 Medical
Oncology Dpt, Hospital General Universitario de Alicante, Alicante, SPAIN,
7 Pathology and Cytopathology Unit, University of Padova, Padova, ITALY,
8 Medical Oncology Service, Catalan Institute of Oncology, Hospital Germans
Trias i Pujol, Badalona, SPAIN
Background: Preclinical and clinical data have shown that low BRCA1 expression
increases sensitivity to platinum. However, the complexity of DNA repair pathways
suggests that the BRCA1 function could be modulated by several proteins. MDC1,
the protein initiating the response to DNA double strand breaks, activates two
parallel pathways: 53BP1 and BRCA1. We hypothesized that the mRNA expression
of components involved in the 53BP1 pathway could influence the predictive value of
BRCA1.
Methods: mRNA expression levels of BRCA1, MDC1, UBC13, RNF8, 53BP1, PIAS4,
MMSET and UBC9 were assessed by real-time PCR analysis in 115
paraffin-embedded tumor samples collected from advanced NSCLC p treated with
first-line platinum-based chemotherapy without taxanes.
Results: Expression levels of BRCA1 were correlated with MDC1 (ρ = 0.47, P <
0.0001), UBC13 (ρ = 0.41, P = 0.001), RNF8 (ρ = 0.41, P = 0.001), 53BP1 (ρ = 0.37,
P = 0.003), PIAS4 (ρ = 0.51, P < 0.0001), MMSET (ρ = 0.57, P < 0.0001) and UBC9
(ρ = 0.31,P = 0.01). Median overall survival (OS) was 11 months (m), and
progression-free survival (PFS) was 7 m. Among p with low levels of BRCA1, median
OS was 19.3 m and PFS was 10 m for p with low levels of 53BP1, compared to 8.2 m
and 5.9 m, respectively, for p with high levels of 53BP1 (OS: P = 0.01; PFS: P <
0.0001). Among p with high levels of BRCA1, no significant differences in OS were
observed according to 53BP1 expression levels.
Conclusions: Advanced NSCLC p with low levels of both BRCA1 and 53BP1 showed
significantly improved outcome to first-line platinum-based chemotherapy. The
assessment of BRCA1 and 53BP1 can be useful for customizing chemotherapy.
Disclosure: All authors have declared no conflicts of interest.
1662P MCPH1 (BRIT1) AND OUTCOME TO ERLOTINIB IN
NON-SMALL-CELL LUNG CANCER (NSCLC) PATIENTS (P)
HARBORING EGFR MUTATIONS
R. Garcia-Campelo 1 , J.J. Sánchez 2 , C. Costa 3 , C. Queralt 4 , I. De Aguirre 4 ,
M.A. Molina, 3 , M. Majem 5 ,S.Cros 4 , L. Capdevila 4 , R. Rosell 4
1 Oncology, Complejo Hospitalario Universitario A Coruña, A Coruña, SPAIN,
2 Statistics, Autonomous University of Madrid, Madrid, SPAIN, 3 Laboratoy of
Biology Department, Pangaea Biotech, USP Dexeus University Institute,
Barcelona, SPAIN, 4 Medical Oncology Service, Catalan Institute of Oncology,
Hospital Germans Trias i Pujol, Badalona, SPAIN, 5 Oncology, Hospital de Sant
Pau, Barcelona, SPAIN
Background: Progression-free survival (PFS) in EGFR-mutant NSCLC p treated with
erlotinib can range from a few months (m) to more than two years, but genetic
influences on the duration of response remain unclear. The cytotoxic effect of
erlotinib has been related to several proteins that regulate DNA damage response (eg,
BRCA1, BRCA2). MCPH1 contains 3 BRCT domains which are conserved in
important molecules involved in DNA damage signaling, including BRCA1, MDC1
and 53BP1. MCPH1 binds to BRCA2 and regulates the localization of BRCA2 and
Rad51 at sites of DNA damage. MCPH1 also regulates the ATP-dependent SWI-SNF
chromatin remodeling complex during DNA repair.
Methods: We used the NanoString nCounter gene expression system, which captures
and counts individual mRNA transcripts, to analyze the expression of 44 selected genes,
many of which are involved in DNA damage response, in 55 erlotinib-treated NSCLC
p. We identified MCPH1 and correlated expression levels with clinical outcomes.
Results: p characteristics: 16 males, 39 females (70.9%); 39 never-smokers (70.9%),
12 former smokers, 4 current smokers; 34 with EGFR deletion in exon 19 (61.8%),
21 with L858R mutation (38.2%). PFS was not reached for patients with high
MCPH1, while it was 19 m for those with intermediate levels and 9 m for those with
low levels (P = 0.01). Median survival was 31 m for p with high levels, not reached
for p with intermediate levels and 17 m for p with low levels (P = 0.004).
Conclusions: The enhanced effect of erlotinib in the presence of elevated MCPH1
could be due to the fact that MCPH1 can interfere with the function of MDC1 and
53BP1. The role of MCPH1 merits validation as a predictive marker of erlotinib
response.
Disclosure: All authors have declared no conflicts of interest.
1663P THE ROLE OF HEDGEHOG (HH) SIGNALING IN THE
PREDICTION OF CLINICAL OUTCOME FOR ADVANCED
NON-SMALL CELL LUNG CANCER (NSCLC)
R. Berardi 1 , A. Santinelli 2 , M. Caramanti 1 , A. Savini 1 , A. Onofri 1 , T. Biscotti 2 ,
A. Brunelli 3 , P. Mazzanti 1 , I. Bearzi 4 , S. Cascinu 1
1 Clinica di Oncologia Medica, AOU Ospedali Riuniti Ancona Università
Politecnica delle Marche, Ancona, ITALY, 2 Anatomia Patologica, AOU Ospedali
Riuniti Ancona Università Politecnica delle Marche, Ancona, ITALY, 3 Thoracic
Surgery, AOU Ospedali Riuniti Ancona, Ancona, ITALY, 4 Anatomia Patologica,
AOU Ospedali Riuniti Ancona Università Politecnica delle Marche,, Ancona,
ITALY
Background: NSCLC lacks validated biomarkers to predict clinical outcome. The Hh
pathway is critical for cell growth and differentiation. The aim of our study is to
evaluate the role of the Hh signaling pathway in determining prognosis of NSCLC
patients.
Methods: In this single-center prospective study, the expression of Hh-related
molecules including Ptch1 and Gli1 (nuclear and cytoplasmic) was determined by
immunohistochemistry in 35 histologic samples (biopsies and surgical specimens) of
advanced NSCLC patients. All the neoplastic area included in the slides was
considered and both cytoplasmic and nuclear stainings were evaluated, according to
the positive neoplastic cells. The intensity of the staining was considered and scored
as 0 (absent), 1+ (low), 2+ (medium) and 3+ (high).
Results: We analyzed 18 adenocarcinomas and 17 squamous cell carcinomas.
Positivity of Gli1-cytoplasmic expression and Gli1-nuclear expression were expressed
in adenocarcinoma at a significantly higher level and more frequently than compared
to squamous cell carcinoma (p < 0.05), while Ptch1 did not differ significantly in the
two histotypes. Overall survival was higher in Gli1 and Ptch1 negative tumor samples
compared to the positive group (p = 0.02). The 18 patients with adenocarcinoma
received erlotinib as second line therapy and those presenting a lower Gli1 and Ptch1
expression experienced a significantly better progression free survival.
Conclusion: At our best knowledge this is the first study investigating the role of HH
in NSCLC patients. The results suggest that the Hh pathway might play a major
prognostic role in NSCLC with significant differences between the histotype.
Furthermore it might predict the efficacy of erlotinib as second-line treatment in
patients with advanced lung adenocarcinoma.
Disclosure: All authors have declared no conflicts of interest.
1664P PROTEOMIC AND CIRCULATING FREE DNA ANALYSIS
OUTCOME PREDICTORS IN THE GALAXY TRIALTM
(NCT01348126): A RANDOMIZED PHASE IIB/III STUDY OF
GANETESPIB (STA-9090) IN COMBINATION WITH
DOCETAXEL VERSUS DOCETAXEL ALONE IN SUBJECTS
WITH STAGE IIIB/IV NSCLC
D. Fennell 1 , E. Petricoin 2 , J. Shaw 3 , I. El Hariry 4 , V. Vukovic 5 , F. Teofilovici 5 ,
V. Reichert 4 , R. Rosell 6
1 Medicine, University of Leicester, Leicester, UNITED KINGDOM, 2 Applied
Proteomics and Molecular Medicine, George Mason University, Manassas, VA,
UNITED STATES OF AMERICA, 3 Cancer Studies & Molecular Medicine,
University of Leicester, Leicester, UNITED KINGDOM, 4 Oncology, Synta
Pharmaceuticals, Lexington, MA, UNITED STATES OF AMERICA, 5 Clinical
Development, Synta Pharmaceuticals Corp., Lexington, VA, UNITED STATES OF
AMERICA, 6 Medical Oncology Service, Catalan Institute of Oncology ICO
Badalona Hospital Germans Trias i Pujol, Medical Oncology, Badalona, SPAIN
Background: Inhibition of Hsp90, a key molecular chaperone required for activation
of many oncoproteins, can lead to cancer cell death. Ganetespib (G) is an Hsp90
inhibitor that has shown single agent activity in molecularly defined disease,
including ELM4-ALK rearrangement, KRAS mutations, HER2 amplification and
Volume 23 | Supplement 9 | September 2012 doi:10.1093/annonc/mds417 | ix533