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ESMO-ESP Joint Symposium:
Molecular diagnostics for personalized
cancer treatment
116IN NEXT GENERATION SEQUENCING IN THE CONTEXT OF
CURRENT CLINICAL PRACTICE: IMPLEMENTATION AND
CHALLENGES
H. Morreau
Leiden University Medical Center, Leiden, NETHERLANDS
In the era of personalized medicine next generation sequencing (NGS) of normal
and/or tumor DNA has already proven its value in the discovery phase of novel
molecular defects associated with human disease. Different levels of information can
be obtained from transcriptome sequencing, whole genome sequencing, exome
sequencing, and sequencing of DNA enriched for methylated DNA. It is expected by
many that soon the NGS sequencing will take its place in current clinical practice
giving diagnostic, prognostic or predictive information. The complex biology
underlying human disease is however now more and more surfacing. Already from
the relatively simple tests using single biomarker sets, but now also from the
discovery phase NGS reports, it became clear that tumor heterogeneity is a major
issue in clinical practice. Although some advocate that the solution should be to
screen all metastasized lesions, obtaining those will be burdensome for patients. How
to use such knowledge on heterogeneous DNA alterations in metastatic lesions for
clinical decision making is also not so easily answered. In current clinical practice we
see that with the success of neo-adjuvant therapies for rectum-, esophagus-, stomach
and breast cancers much of the molecular analyses should be done on limited
material. With innovative methods, such as ultrasound guided trans-bronchial or
trans- esophageal needle aspiration for staging of lung cancer combined with
molecular analysis on very limited amounts of cancer cells, a similar trend can be
seen. Although technical advances coming from e.g. single cell sequencing efforts can
be applied it should be realized that such approaches can lead to diagnostic errors in
true clinical practice. Therefore major quality assurance programs should be initiated
before NGS can truly take its predicted role.
Disclosure: The author has declared no conflicts of interest.
117IN BIOMARKER DEVELOPMENT NEEDS TISSUE
REPOSITORIES: NO HONEY WITHOUT BEES
H. Lehr
IUP Institut Universitaire de Pathologie de Lausanne, Lausanne, SWITZERLAND
Pathologists have traditionally archived the tissues on which they have established the
diagnoses for their patients. Like many other professional societies, the Swiss Society
for Pathology has recommended that paraffin blocks be retained for a minimum of
20 years (40 years for pediatric tumors). In addition to paraffin blocks, fresh tumor
and non-tumorous tissues can be frozen rapidly and kept for many years in freezers
at -80°C or in nitrogen tanks. The research value of these archived tissues depends
largely on the disposition of clinical information, on patient survival, and – ideally –
on data concerning tumor response to treatment (chemotherapy, targeted
treatments). With this information, combined with the modern tools of molecular
pathology, notably deep sequencing, novel cancer markers with prognostic and/or
predicitve values can be detected in historic cohorts and verified in independent
historic cohorts, before ultimately being tested prospectively in “new” cancer patients
(the “honey”). Certainly, this can only be successful, (i) if the material is adequately
stored and quality-controlled (is there truely invasive carcinoma in the tissue block
?), (ii) if the logistics for clinical data management is professionally organized, and
(iii) if there exists an understanding and a consent of the patients whose tissues are
to be used for research. The first two tasks lay in the hands of professionals who run
the bank (pathologists, technicians, data managers), and have to be compensated for
their work (the “bees”). The third task needs to be solved at the level of the general
population. The last few years have seen many fruitful discussions and conferences
dedicated to establishing a consensus between the general population (patients) and
the scientific community (researchers). A recent survey among 1600 French- and
German-speaking Swiss citizens has shown that the population is highly- and quite
unconditionally - in favor of biobanking for research, provided that patients are
properly informed and that their (written) consent is asked.
Disclosure: The author has declared no conflicts of interest.
118IN KRAS AND COLORECTAL CANCER: WHAT’S NEXT?
No abstract submitted at time of going to press.
Annals of Oncology 23 (Supplement 9): ix61, 2012
doi:10.1093/annonc/mds485
119IN MOLECULAR TYPING OF LUNG CANCER: MORE PIECES TO
THE PUZZLE
S. Peters
Oncology, Centre Hospitalier Universitaire Vaudois - CHUV, Lausanne,
SWITZERLAND
Distinct subtypes of NSCLC, so-called “oncogene addicted”, are driven by a specific
genetic alteration sustaining tumor proliferation and survival – and are thus sensitive
to inhibition of the corresponding activated pathway. This new paradigm has
substantially impacted treatment from standard chemotherapy customized patient
characteristics, expected toxicity and histological subtype to molecularly driven
approaches in advanced NSCLC. Nowadays, adenocarcinoma - but also squamous
carcinoma in recent reports - can be further subdivided into numerous clinically
relevant molecular subsets. EGFR activating mutations or EML4-ALK translocation
have been shown to be associated with better outcome when targeted by dedicated
molecules. Treatment of patients with EGFR activating and sensitizing
mutations-driven NSCLC with EGFR tyrosine kinase inhibitors (TKIs) results in an
unprecedented response rate (RR) of 60-80%, a median progression free survival
(PFS) of approximately 8-13 months, as well as an improved quality of life (QoL)
compared to chemotherapy. This was the first and a strong illustration of the
therapeutic relevance of molecular classification of NSCLC. In NSCLC, ALK
rearrangement has at least 3 reported fusion partners: EML4, KLC1, and KIF5B. In
these tumors, ALK is the sole determinant of critical growth pathways, resulting in
activation of downstream canonical PI3K/AKT as well as MAPK/ERK pathways.
Within the pivotal phase 1/2 clinical trial, treatment of 82 EML4-ALK positive
patients with crizotinib resulted in a 57% RR and median PFS was 10 months. The
kinetics of clinical response were comparable to previous experiences with EGFR
TKIs in EGFR-mutated NSCLC. Other transforming genetic alterations have been
identified such as MET, Her2 and FGFR1 amplification, KRAS, NRAS, BRAF, MEK1,
AKT1, PIK3CA, AKT, FGFR2, DDR2, PTEN and HER2 mutations, RET, ROS1 and
ALK rearrangements. While every distinct alteration remains a rare event per se in
our NSCLC population, their frequency was shown to vary according to histological
subtype, and defined clinical characteristics including smoking history, gender and
ethnicity. All of them have to be subject of future epidemiological, fundamental,
translational as well as clinical research in order to propose more active treatments to
patients in the future.
Disclosure: The author has declared no conflicts of interest.
Volume 23 | Supplement 9 | September 2012 doi:10.1093/annonc/mds485 | ix61