Advances in Personalized Medicine for Lung Cancer

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                                         PRESS RELEASE
                     EMBARGOED until 18 April 2012, 12:00 hours (CEST)

               Advances in Personalized Medicine for Lung Cancer
                  Presentations at the 3rd European Lung Cancer Conference

Lugano-CH/Aurora-US-CO/Geneva-CH, 18 April 2012 -- Several new studies that may help
doctors tailor lung cancer treatment to the characteristics of individual patients and of their tumors
are being presented at the 3rd European Lung Cancer Conference in Geneva.

“A major goal of lung cancer treatment is to tailor the treatment to the individual,” says Dr Fiona
Blackhall from The Christie NHS Foundation Trust in Manchester, UK. “The studies that will be
presented at ELCC 2012 are important practical steps to achieving this in the clinic. Methods
ranging from convenient blood-based molecular tests, detailed genetic analysis of tumors and
functional imaging techniques have been applied in patient populations receiving a range of
treatments. These findings provide impetus to continue developing a personalized medicine
approach to lung cancer with the overall aim of selecting the most effective treatment for the

Proteins provide clues to outcomes
An international group of researchers report promising results with a test that may identify patients
likely to benefit from first-line therapy with a particular drug combination.

Dr Oliver Gautschi from the Swiss Group for Clinical Cancer Research (SAKK), and collaborators
from The Netherlands and the US company developing the test, conducted a retrospective
analysis of two phase-II trials with a serum proteomic classifier called VeriStrat®. Their aim was to
evaluate the prognostic value of the test in patients with advanced non-small cell lung cancer
receiving first-line treatment with bevacizumab and erlotinib.

VeriStrat® uses mass spectrometry to measure proteins in pre-treatment blood and assigns a
result that correlates with outcome from treatment with a class of drugs known as EGFR inhibitors,
which includes erlotinib and gefitinib. The test was initially developed and validated in patients who

had already been treated with chemotherapy, and who then received an EGFR inhibitor in second
line, Dr Gautschi explains.

“We conducted this project to see if the test is also prognostic in untreated patients who received
an EGFR inhibitor in the first line. Until now, this has not been clear.”

The researchers used VeriStrat® to analyze blood samples from 117 patients previously enrolled
in two phase II trials and compared the results to the patients’ progression-free survival and overall
survival. The analysis showed that those classified by the test as likely to have better outcomes on
EGFR inhibitor therapy did indeed live longer.

“The difference in overall survival between patients classified by the test as likely to have better or
worse outcomes when receiving EGFR inhibitors was clinically relevant,” Dr Gautschi said.
However he noted that definitive conclusions about the use of this test in previously untreated
patients requires further studies.

”There is an unmet need for reliable blood-based markers in patients with lung cancer, because
lung tumors are harder to biopsy than breast tumours for example. The current study indicates that
modern technologies, such as proteomics, are promising tools, which need further validation in
large trials,” he said. In this context, the European Thoracic Oncology Platform (ETOP) is currently
launching a prospective phase-III trial to futher validate this test in patients with lung cancer.

“Clinical trials involving robust predictive tools have potentially a great impact and can be of
paramount relevance in defining the real role of personalized cancer medicine,” commented Dr
Rafael Rosell from the Catalan Institute of Oncology in Badalona, Spain, member of the ESMO
Chest Tumors Faculty group. “This broad proteomic analysis can provide useful information,
circumventing the problem of tumor heterogeneity that can arise when a single tumor biopsy is
examined,” Dr Rosell added.

Micro RNA marks response to chemoprevention
Dr Celine Mascaux from the University of Colorado and collaborators report that the micro RNA
miR-34c is a potential biomarker for histological response in lung cancer chemoprevention studies.

Chemoprevention is a way of preventing the development of cancer using medicines or other
agents, including the prevention of cancer in at-risk individuals such as smokers.

Currently, the best intermediate endpoint for studies of chemoprevention is a histological grading of
cells in the airways of the lungs. However, as Dr Mascaux’s group notes, “more quantitative
biomarkers of response would be desirable.”

Dr Mascaux and colleagues analyzed the expression of selected micro RNAs as potential
surrogate biomarkers in a lung cancer chemoprevention trial that compared a drug called iloprost
to placebo in 125 former or current smokers.

In a recent study, oral iloprost has shown promise to prevent the development of lung cancer in
high-risk people.

After analyzing 14 different micro RNAs from 496 lung biopsies, they found that change in the
expression of a particular micro RNA -- miR-34c -- in follow-up biopsies was inversely correlated
with histological response.

Changes in the expression of this micro RNA may therefore be a quantitative biomarker of
response in lung chemoprevention studies, they say.

RRM predicts shorter survival
Dr Giovanna Dal Bello and colleagues report that expression levels of ribonucleotide reductase
subunit 2 (RRM2) predict shorter survival in patients whose non-small cell lung cancer had been
surgically removed. In 82 patients, the Italian group found that RRM2 was an independent
prognostic marker of shorter survival.

“The difference in overall survival between patients with high or low RRM2 levels was clinically
relevant,” said Dr Dal Bello from the National Institute for Cancer Research in Genoa, Italy. “In
particular, mean survival time of patients with high RRM2 levels was 36.5 months compared to
46.1 months for those with low RRM2 levels.”

“This is the first study that identifies RRM2 expression as a negative prognostic factor in resected
stage I-III NSCLC,” they report.

“RRM2 was identified as an unfavorable prognostic marker in our study population and this is in
agreement with its crucial role in supplying deoxyribonucleotides for DNA synthesis and repair and
with the finding that cells overexpressing RRM2 exhibit enhanced cellular invasiveness,” Dr Dal
Bello explained.

Because of the high and rapid recurrence rate of lung cancer, prognostic markers to identify
patients with higher risk of relapse represent a high unmet medical need. “The prognostic role of
RRM2 can help to identify patients at higher risk of relapse who may benefit from adjuvant
chemotherapy,” she noted.

Epigenetic clues distinguish tumor types
Dr David Shames from a San Francisco, California–based biotechnology company[1] and
colleagues report that epithelial-like lung tumors, which have a better prognosis and exhibit greater
sensitivity to inhibitors of the EGFR pathway, can be distinguished from mesenchymal-like tumors
on the basis of global DNA methylation patterns.

DNA methylation is an important form of ‘epigenetic’ modification, which affects the expression of
genes within cells.

Using cancer cell lines and surgically resected non-small cell lung cancer tumors, the researchers
showed that patterns of DNA methylation can divide non-small cell lung cancer into two
phenotypically distinct subtypes.

Their work also provides proof of principle, they say, that “differences in DNA methylation can be
used as a platform for predictive biomarker discovery and development.”

A promising biomarker of response to radiotherapy
In a further report, Dr Ioannis Trigonis from the Wolfson Molecular Imaging Centre and The
Christie Hospital in Manchester, UK, describes the findings from an assessment of F-18
fluorothymidine (FLT), a tracer molecule used in PET scanning to measure tumor cell proliferation.

Dr Trigonis’ group studied 14 patients with NSCLC who had a total of 31 dynamic FLT PET-CT
scans before and within 1-2 weeks after the start of radical radiotherapy. They found that
radiotherapy induced early significant decreases in tumor FLT uptake that varied across patients.

Their results indicate the potential of FLT PET to identify how well patients are responding to
radiotherapy and guide therapeutic approaches, they say. More results will be presented at the

Notes to Editors
[1] Dr David Shames is an employee of the Oncology Biomarker Development division of Genentech Inc.
Information contained in this press release was provided by the abstract's authors and reflects the content of the studies.
It does not necessarily express ESMO's or IASLC’s point of view.
About the European Lung Cancer Conference (ELCC) 2012
The European Lung Cancer Conference (ELCC) has become the reference event in Europe for professionals treating
lung cancers. From surgical resection to complex treatment options with novel agents and novel targets; from lung
cancer in non-smokers to issues surrounding gender; from various forms of lung cancer, the big killer, to rare forms of
chest tumors: the third edition of the ELCC provides a comprehensive multidisciplinary overview of the latest as well as
of the state-of-the-art knowledge in thoracic malignancies, covering different aspects such as prevention, screening,

diagnosis, treatment modalities and the results of basic, clinical and translational research, presented by top international
academic experts. More than 1,500 attendees are expected from throughout Europe and the rest of the world.

About the European Society for Medical Oncology (ESMO)
The European Society for Medical Oncology (ESMO) is the leading European professional organization committed to
advancing the specialty of medical oncology and promoting a multidisciplinary approach to cancer treatment and care.
ESMO’s mission is to advance cancer care and cure through fostering and disseminating good science that leads to
better medicine and determines best practice.
As a trusted organization with 35 years of experience, ESMO serves its members and the oncology community through:
a brand of excellence in post-graduate oncology education and training; leadership in transforming evidence-based
research into standards of cancer care in Europe; dedicated efforts to foster a more favorable environment for scientific
research; innovative international platforms to share expertise, best practices and disseminate the most up-to-date
scientific research to as wide an audience as possible.
ESMO’s scientific journal, Annals of Oncology, ranks among the top clinical oncology journals worldwide. ESMO events
are the meeting place in Europe for medical oncologists to update their knowledge, to network and to exchange ideas.
To find out more about ESMO, please visit:

About the International Association for the Study of Lung Cancer (IASLC)
The International Association for the Study of Lung Cancer (IASLC) is the only global organization dedicated to the study
of lung cancer. Founded in 1974, the association’s membership includes more than 3,500 lung cancer specialists in 80
countries. To learn more about IASLC please visit

Abstract 80O
Translational research, biology and pathology
Proffered Paper session: Friday, 20 April, 14:30-16:00, Room C

Serum proteomic classifier for patients with advanced non-small cell lung cancer (NSCLC) treated with erlotinib
and bevacizumab in first line: pooled analysis of phase II trials SAKK19/05 and NTR528

Background: VeriStrat® proteomic classifier is a serum test utilizing mass spectrometry which reports two labels:
VeriStrat Good (VSG) or VeriStrat Poor (VSP). Published data show VSG pts to perform better than VSP pts upon
treatment with EGFR TKIs. We retrospectively explored VeriStrat’s ability to separate pts with advanced non-squamous
NSCLC treated in first-line with bevacizumab and erlotinib (BE) into better and worse progression-free survival (PFS)
and overall survival (OS) groups. Methods: Individual data and archived serum samples from 117 pts previously enrolled
in 2 European phase II trials of first-line BE (NCT00354549 and NTR528) were analyzed. VeriStrat was performed
centrally by Biodesix (USA). PFS and OS were evaluated using the Kaplan-Meier method; groups were compared using
the log-rank test. The hazard ratio (HR) was assessed using Cox proportional hazards (CPH) models. For the
multivariate analyses, both endpoints were analyzed using CPH and stepwise selection to check the importance of
selected factors. Results: Veristrat analysis performed in 117 pts sera from both trials classified 87 (74%) as VSG, 27
(23%) as VSP and 3 (3%) as "indeterminate". VSG and VSP demonstrated a statistically significant difference in OS
(p=0.0027, HR=0.480, 95% confidence interval (CI): 0.294–0.784) but significance for PFS was not reached (p=0.2632,
HR=0.768, 95% CI: 0.482-1.223). PFS and OS were also assessed using multivariate analyses on the combined VSG
and VSP pts. Stepwise selection indicated the following associations: age (p<0.0001) and histology (adenocarcinoma
versus large cell carcinoma and not otherwise specified) (p<0.0001) with PFS, VeriStrat classification (p=0.0042) and
smoking status (p<0.0001) with OS. Conclusions: These results support the notion that VeriStrat may be useful for
clinical decision-making, representing a prognostic and potentially a predictive biomarker for treatment with EGFR TKIs.
This predictive value of VeriStrat will be tested in a prospective clinical trial in advanced squamous cell lung carcinoma,
sponsored by the European Thoracic Oncology Platform (ETOP).
Author Block
O. Gautschi1, A.-M. Dingemans2, S. Crowe1, H. Roder3, F. Zappa4, M. Pless5, M. Brutsche6, S. Peters7, D. Carbone8,
E.F. Smit9; 1Bern/CH, 2Maastricht/NL, 3Broomfield/US, 4Lugano/CH, 5Winterthur/CH, 6St. Gallen/CH, 7Lausanne/CH,
8               9
 Nashville/US, Amsterdam/NL

Abstract 137O
Early stage and locally advanced NSCLC
Proffered Paper session: Friday, 20 April, 14:30-16:00, Room K

Imaging early radiotherapy (RT)-induced changes of proliferation in patients with non-small cell lung cancer
Background. [F-18]Fluorothymidine (FLT) is a promising biomarker of response to RT. 2 pilot studies in NSCLC have
reported FLT PET uptake changes at variable time points during concurrent chemo-RT (Everitt 2009, Vera 2011). It is
unknown, whether FLT uptake decreases early during RT alone and whether such changes exceed test-retest variability.
Methods. FLT-PET imaging is performed in NSCLC patients (pts) scheduled for radical RT twice at baseline (scans 1, 2)
to assess reproducibility and after 3-10 RT fractions (scan 3), to assess response. Serial blood samples for analysis of
circulating cell death biomarkers are also taken (M30/65). Data are dynamically acquired for 60min on the TrueV PET/CT
scanner. 45-60 minute images are reconstructed using 3D-OSEM, smoothed with a 4mm Gaussian filter. Tumours are
manually delineated on PET-CT images by a specialist thoracic radiologist. SUV reproducibility is measured as (SUV2-
SUV1)/(SUV1+SUV2)*200. RT response is calculated as % change relative to single/average baseline value.
Results. 14 evaluable pts had a total of 31 scans: 10 male, 4 female, age 47-83, Stage II(1), III (10), III/IV(3) NSCLC
treated with radical RT (12 pts: 55Gy in 20 fractions (#), 1pt: 66Gy in 33#, 1pt: 50Gy in 20#).
5 pts are evaluable for reproducibility and 12 for response. Pre-treatment scans were done within 2-6 days and on-
treatment scans 6-15 calendar days after day1 RT (4-11 fractions, 11-30Gy).
38 lesions were delineated: 14 primary tumours (6-214cm3, median 70cm3) and 24 nodes (2-22cm3, median 7cm3)
Mean absolute SUVmean reproducibility was 8.1% (primaries 7.6%, nodes 8.3%). Following RT malignant lesion
SUVmean change ranged from +3.1 to -53.6% (average -33.6%, primaries -24.9%, nodes -39.4%). SUVmax average
reproducibility was 12.2% and response -36.5%.
Conclusions. RT induces early decreases in tumour FLT uptake which exceed baseline reproducibility. We observed
less average decrease in primary tumour uptake compared to previous report using comparable RT dose but with
concomitant chemotherapy (SUVmax decrease >40%) (Everitt, 2009). Recruitment is ongoing and blood biomarker and
updated imaging, including kinetic, results will be reported.

Author Block
I. Trigonis1, P. Koh1, M.-C. Asselin1, M. Tamal1, B. Taylor1, M. Earl1, O. Ataman2, A. Jackson1, C. Faivre-Finn1, F.
          1 1                 2
Blackhall ; Manchester/UK, Macclesfield/UK

Abstract 83PD
Translational research, biology and pathology I
Poster Discussion session, Saturday, 21 April, 8:00-8:50, Room F

DNA Methylation Profiling Defines Clinically Relevant Biological Subsets of Non-small Cell Lung Cancer

Purpose: NSCLCs comprise multiple distinct biological groups with different prognoses. Patients with epithelial-like (EL)
tumors have a better prognosis and exhibit greater sensitivity to inhibitors of the EGFR pathway than patients with
mesenchymal-like (ML) tumors. Here we test the hypothesis that EL NSCLCs can be distinguished from ML NSCLCs on
the basis of global DNA methylation patterns.
Methods: To determine whether phenotypic subsets of NSCLC can be defined based on their DNA methylation patterns,
we combined microfluidics-based gene expression analysis and genome-wide methylation profiling. We derived robust
classifiers for both gene expression and methylation in cell lines and tested these classifiers in surgically resected
NSCLC tumors. We validate our approach using quantitative RT-PCR and methylation specific PCR in FFPE biopsies.
Results: We show that patterns of methylation divide NSCLCs into EL and ML subsets as defined by gene expression
and that these signatures are similarly correlated in NSCLC cell lines and tumors. We identify multiple DMRs, including
one in ERBB2 and one in ZEB2, whose methylation status is strongly associated with an epithelial phenotype in NSCLC
cell lines, surgically resected tumors, and FFPE biopsies from NSCLC patients who went on to fail front-line
Conclusions: Our data demonstrate that patterns of DNA methylation can divide non-small lung cancers into two
phenotypically distinct subtypes of tumors and provide proof of principle that differences in DNA methylation can be used
as a platform for predictive biomarker discovery and development.

Author Block
D.S. Shames1, K. Walter1, T. Holcomb1, L.C. Amler1, G. Hampton1, R. Yauch1, R. Bourgon2, P. Du2 1Oncology
Biomarker Development, Genentech Inc., South San Francisco, CA, UNITED STATES OF AMERICA, 2Bioinformatics,
Genentech Inc., South San Francisco, CA, UNITED STATES OF AMERICA

Abstract 65O
Prevention, Early detection, Prognosis, Epidemiology, Tobacco control
Proffered Paper session, Thursday, 19 April, 16:20-17:50, Room C

miR-34c is a potential biomarker for histological response in lung cancer chemoprevention studies
Endobronchial histology is currently considered the best intermediate endpoint for chemoprevention studies. While
histologic grading is reproducible between specialized pathologists, more quantitative biomarkers of response would be
desirable. We analyzed the expression of selected miRNA as potential surrogate biomarkers in the Iloprost lung cancer
chemoprevention trial, which is the first to meet a pre-determined primary endpoint of histology improvement (Keith,
Cancer Prev Res 2011).
Matched biopsies (baseline-BL and the same site at follow-up-FU after 6 months of Iloprost or placebo) were obtained in
125 high-risk individuals who completed the trial: 40/35 and 25/25 current/former smokers in the Iloprost and placebo
arm, respectively. We analyzed 496 biopsies including 4 matched biopsy pairs per patient: the best and the worst
histology at BL and the 2 biopsies from same site at FU. Total RNA was extracted from formalin fixed paraffin embedded
sections adjacent to the diagnostic section and 14 selected miRNA previously identified in high-grade bronchial
preneoplasia were analyzed by qRT-PCR (Mascaux, Eur Resp J 2009).
In the earlier and current studies, miR-34c expression was inversely correlated with BL histology grade (r=0.36, p<0.001,
false discovery rate (FDR) <0.1). The current study demonstrated that the change in miR-34c expression between BL
and FU biopsies was also inversely correlated with histology changes (r=0.23 p=0.0003, FDR<0.1) and this was
independent of treatment arm or smoking status. In addition, a lower miR-34c expression at BL, and consequently its
increase at FU, was significantly associated with histological response in the Iloprost (p=0.0022, FDR<0.1) and placebo
arms (p=0.0025, FDR<0.1).
The changes in miR-34c (a transcriptional target of p53) expression were inversely correlated with histological changes
at FU. In responders, miR-34c expression is significantly lower at BL and increased at FU, related with a worse histology
at BL and its down-grading at FU. We conclude that the change in miR-34c expression in FU biopsies is correlated with
histological response and may be a quantitative biomarker of response in lung chemoprevention studies.

Author Block
C. Mascaux, R.L. Keith, W.J. Feser, M.T. Lewis, A.E. Barón, D.T. Merrick, W.A. Franklin, P. Bunn, Y.E. Miller, F.R.
Hirsch; Aurora, CO/US

Abstract 79O
Translational research, biology and pathology
Proffered Paper session, Friday, 20 April, 14:30-16:00, Room C

Ribonucleotide reductase subunit 2 (RRM2) predicts shorter survival in resected stage I-III non-small cell lung
cancer (NSCLC) patients
Background: Biomarkers can help in identifying patients (pts) with early-stage NSCLC with high risk of relapse and bad
prognosis. The aim of this study was to investigate the relationship between the levels of expression of 7 biomarkers,
clinicopathological characteristics and their prognostic significance.

Methods: Tumor tissue from 82 radically resected stage I-III NSCLC pts were consecutively collected to investigate the
mRNA expression and protein levels of the following biomarkers: excision repair cross-complementation group 1

(ERCC1), breast cancer 1 (BRCA1), ribonucleotide reductase subunit 1 (RRM1), RRM2, p53R2, thymidylate synthase
(TS) and class III beta-tubulin (β-Tub-III) using quantitative reverse transcriptase real-time PCR (qRT-PCR) and
immunohistochemistry (IHC) with tissue microarray technique.

Results: In univariate analysis, p53R2 expression was significantly higher in adenocarcinoma (ADK) compared to
squamous cell carcinoma (SSC) samples (p=0.002) and in stage I compared to stage II-III (p≤0.001). ERCC1 expression
was significantly higher in female compared to male (p=0.03) and β-Tub-III expression was significantly higher in ADK
than in SSC (p=0.03). Pts with lower RRM2 expression survived longer than pts with higher RRM2 expression (p=0.069).
The multivariate analysis confirmed RRM2 as an independent prognostic marker of shorter survival (p= 0.031). The
comparison of survival curves with qRT-PCR and IHC showed that there was similar results with a trend towards longer
survival among ERCC1 negative pts, BRCA1 negative, p53R2 positive and among pts with low levels of RRM1 and
RRM2 although the difference was not statistically significant in both methods. qRT-PCR and IHC have shown that β-
Tub-III and TS had no significant impact on survival.

Conclusions: This is the first study that identifies RRM2 expression as a negative prognostic factor in resected stage I-III
NSCLC. Moreover, we have demonstrated the different expression of p53R2 and β-Tub-III in ADK compared to SSC and
higher expression of p53R2 in stage I compared to stage II-III pts.

Author Block
M.G. Dal Bello, G. Savarino, E. Rijavec, C. Sini, G. Barletta, C. Genova, M. Truini, D. Merlo, U. Pfeffer, F. Grossi;


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