Annals of Oncology

abstracts
a strong need of reliable biomarkers for providing information about the molecular
events that occur in early stage of NSCLC.
Methods: We analyzed a ten-year series of 167 consecutive formalin fixed stage I
NSCLCs. We included 67 squamous cell carcinomas (SCC) and 100 adenocarcinomas
(ADC). Mutation analysis of 10 genes involved in NSCLC (EGFR, KRAS, BRAF,
PIK3CA, NRAS, ALK, ERBB2, DDR2, MAP2K1 and RET) was performed by
MALDI-TOF Mass Spectometry (MassARRAY, Agena Bioscience) using the Myriapod
Lung Status Kit (Diatech Pharmacogenetics). Tumor LINE-1 methylation status was
determined by PCR-pyrosequencing on bisulfite-treated DNA and compared with
normal lung tissue.
Results: In ADCs we identified 29 KRAS (29%), 17 EGFR (17%), two BRAF (2%) and
one PIK3CA mutations (1%). Considering the smoking habit, we observed that all the
KRAS mutations clustered in NSCLC from smoker patients. The never-smoker group
only showed EGFR mutations. In SCCs, we identified four non-canonical mutations in
EGFR gene (6%), and four mutation in PIK3CA (6%). NSCLC showed methylation
levels ranging from 14.8% to 78.8% while normal tissue had percentages from 66% to
76.4%. The mean LINE1 methylation value was significantly lower in NSCLC than in
normal lung (p = 0.0025). A strong LINE-1 hypomethylation was observed in SCC
compared with ADC samples (p < 0.0001). Moreover, a positive association between
LINE-1 hypomethylation and smoking habit was observed (p = 0.0003).
Conclusions: The mutation pattern typical of advanced disease is observed also in
stage I NSCLC patients who may deserve tailored adjuvant target therapy. LINE-1
hypomethylation occurs early in NSCLC and is specifically associated with smoking
habit and with SCC histology. Genetic and epigenetic events represents two
complementary mechanisms in cancer and the knowledge of both types of alterations
in NSCLC opens the possibility of new combinations of therapeutic agents.
Legal entity responsible for the study: University of Insubria
Funding: University of Insubria
Disclosure: All authors have declared no conflicts of interest.
Annals of Oncology
mutated breast cancer patient, the clinical efficacy of treatments targeting ERBB3
mutations remain largely unknown 1 . The objective of our study was to evaluate the
efficacy of approved HER3 partners’ inhibitors in the ERBB3 mutant population.
Methods: We retrospectively evaluated the clinical efficacy of HER3 partner’s inhibitor
in ERBB3 mutant tumors. ERBB3 mutations were detected using Targeted Gene Panel
Sequencing in patients enrolled in our molecular screening program (MOSCATO 01).
Results: Mutations in ERBB3 were observed in less than 2% of the cases (12 patients)
in various tumor types: head and neck SCC (2), biliary tract carcinoma (2), a rectal
neuroendocrine tumor, an urothelial bladder carcinoma, a clear cell adenocarcinoma of
the cervix, a carcinoma of unknown primary, a lung SCC, an invasive lobular breast
carcinoma and a pterygoid sarcoma. Overall, 7 patients received HER3 partners’
inhibitors (trastuzumab and/or lapatinib or afatinib), 4 patients received other
molecularly targeted agents (mTOR, PI3K or NOTCH inhibitors) and one failed being
treated. We observed 1 partial response (PR) with the association of
trastuzumab + lapatinib for a biliary tract carcinoma patient and 1 PR for a HNSCC
patient with torisel. Out of 6 patients with stable disease (SD), the breast cancer patient
had 504 days on xeloda + lapatinib association, and the lung SCC patient had 420 days
on afatinib. When the mutation was located in the tyrosine kinase domain (TKD),
patients were highly sensitive to HER3 partners’ inhibitors, compared to mutations out
of the TKD (hazard ratio for PFS = 6.63, p value = 0.01). Conversely, poor treatment
efficacy was associated with the following parameters: mutations in the extracellular
domain, >2 coexisting driver alterations, and > 1 previous systemic treatment line.
Conclusions: This preliminary data supports the role of ERBB3 as an oncogenic driver.
Larger cohorts of patients with ERBB3 mutations will be required to further identify
and validate characteristics that drive sensitivity to HER3 partners’ inhibitors.
Legal entity responsible for the study: Gustave Roussy Cancer Campus
Funding: Gustave Roussy Cancer Campus
Disclosure: All authors have declared no conflicts of interest.
121P
Screening of significant oncogenic changes in air
pollution-related lung cancer in a Xuanwei County, China
123P
Signal transducer and activator of transcription–3 (STAT3)
expression concordance in paired primary and metastatic
colorectal cancers (mCRC)
M. Kanwal 1 , X. Ding 1 ,C.Yi 1 , Y. Huang 2
1 Laboratory of Molecular and Experimental Pathology, Kunming Institute of
Zoology, Kunming, China, 2 Department of Thoracic and Cardiovascular Surgery,
Yunnan Tumour Hospital (3rd Affiliated Hospital Affiliated to Kunming Medical
College), Kunming, China
Background: Air pollution-related lung cancer has been considered as an exacerbating
public health problem worldwide, particularly in developing countries. Xuanwei and
Fuyuan County in Yunnan, China, regions with severely polluted air and exceptionally
high lung cancer rates, are considered as good models to study air pollution-related
lung cancer. The objective of the study was to establish a simple and sensitive test to
define the status of clinically significant oncogenes in air pollution-related lung cancer.
Methods: This study investigated the expression and mutation of HER2, and fusion
gene EML4-ALK, CD74-ROS1 prevalence in lung cancer patients by reverse
transcription PCR (RT-PCR) and DNA sequencing.
Results: Of the 82 patients with non-small cell lung cancer, 20.7% (17/82) exhibited
HER2 up-regulation, and 1.2% (1/82) harbored HER2 insertion at exon 20. HER2
overexpression was not associated with air pollution levels and smoking status; 6.1% (5/
82) showed ALK gene rearrangements, two belonged to EML4-E2 + ALK-E20 and
three were EML4-E13 + ALK-E20; 3.6% (3/82) carried the CD74-ROS1 fusion gene
(CD74-E6 + ROS1-E34). EML4-ALK fusion was found associated with smoking or a
heavily polluted region, while CD74-ROS1 fusion occurred more frequently in
non-smokers and in low polluted areas.
Conclusions: The screening of HER2 overexpression and EML4-ALK fusion is helpful
to guide treatment of air pollution-related lung cancer; the proposed RT-PCR-based
test could be a useful tool in clinical applications to screen these genetic changes.
Legal entity responsible for the study: N/A
Funding: Natural Science Foundation of China (grant number 81272617)
Disclosure: All authors have declared no conflicts of interest.
122P
Clinical efficacy of HER3 partners’ inhibitors in ERBB3
mutated cancer patients
L. Verlingue 1 , C. Massard 1 , A. Hollebecque 1 , E. Castanon Alvarez 1 ,
S. Postel-Vinay 1 , E. Angevin 1 , J-P. Armand 1 , S. Aspeslagh 1 , A. Varga 1 ,
B. Ratislav 1 , A. Gazzah 1 , J-M. Michot 1 , L. Lacroix 2 , T. De Baere 3 , A. Marabelle 1 ,
J-C. Soria 4
1 Drug Development Department (DITEP), Institut Gustave Roussy, Villejuif, France,
2 Laboratoire de Recherche Translationnelle et Centre de Ressources Biologiques,
Institut Gustave Roussy, Villejuif, France, 3 Interventional Radiology, Institut Gustave
Roussy, Villejuif, France, 4 Drug Development Department (DITEP), Gustave
Roussy, University Paris-Saclay, Villejuif, France
D. Yokom 1 , S. Sud 2 , H. Marginean 2 , T. Asmis 2 , D.J. Jonker 2 , G. Martel 3 ,
A. Gown 4 , M. Daneshmand 5 , E.C. Marginean 5 , R. Goodwin 2
1 Division of Medical Oncology, Princess Margaret Hospital, Toronto, ON, Canada,
2 Division of Medical Oncology, The Ottawa Hospital Regional Cancer Centre,
Ottawa, ON, Canada, 3 Department of General Surgery, The Ottawa Hospital
Regional Cancer Centre, Ottawa, ON, Canada, 4 Department of Pathology,
PhenoPath, PLLC, Seattle, WA, USA, 5 Department of Pathology, The Ottawa
Hospital Regional Cancer Centre, Ottawa, ON, Canada
Background: STAT3 is a constitutively activated transcription factor in several cancers.
In patients with mCRC overexpression of STAT3 is associated with worse survival. To
determine if STAT3 is a potential target for therapy and to evaluate expression through
metastatic progression in mCRC the concordance of expression in primary and
metastatic tumors was assessed.
Methods: Patients treated at the Ottawa Hospital from 2001-2012 were retrospectively
identified and included if tumor tissue was available from both the primary and a
metastasis. Tissue microarrays were constructed using 2 x 2mm cores for each tumor.
Nuclear phosphorylated STAT3 expression intensity by immunohistochemistry was
evaluated by 2 independent pathologists as 0 (absent), 1-2 (low), or 3 (high). The
primary outcome was concordance of STAT3 expression between primary and
metastatic sites. Secondary outcomes included correlation of STAT3 expression with
demographic and disease characteristics as well as clinical outcomes.
Results: Among 38 patients identified 52% were male, median age at diagnosis was 61,
and 36% of metastases were synchronous. Expression of STAT3 in primary tumors was
5% high, 42% low and absent in 53% compared to 16% high, 47% low, and 37% absent
in metastatic samples. Expression between paired primary and metastatic samples was
concordant in 33% of patients whereas it increased in 21% and decreased in 45%. A
weak correlation was observed between primary and metastatic STAT3 expression
(Pearson’s correlation 0.1). After a median follow-up of 13.1 years, 30 of 35 patients
included in the survival analysis died. Median survival was 4.6 years. Higher STAT3
expression in primary tumors showed a trend towards worse survival (HR 1.7, 95% CI
0.81-3.64, p = 0.1), while there was no prognostic correlation of STAT3 expression in
metastases.
Conclusions: In patients with mCRC there was low concordance of STAT3 expression
in primary and metastatic tumors. STAT3 expression in the primary, but not the
metastatic site, was related to survival, indicating that the prognostic value of STAT3
depended on tumor sampling. These results have important implications for further
research in the use of STAT3 as a biomarker in patients with mCRC.
Legal entity responsible for the study: Ottawa Hospital Research Institute
Funding: The Ottawa Hospital Department of Medicine
Disclosure: All authors have declared no conflicts of interest.
Background: Mutations affecting ERBB3 are rare but diffuse across cancer types.
Besides the case report of an effective treatment by HER2 double blockade in an ERBB3
vi36 | abstracts Volume 27 | Supplement 6 | 2016