development of innovative approaches for the non- invasive
TRANSCRIPT
Development of innovative approaches for the non-
invasive monitoring of disease response and
resistance to tyrosine-kinase inhibitors in liver and
lung cancer
Romano Danesi
Department of Clinical and
Experimental Medicine
University of Pisa
Rodolfo Sacco
Department of
Gastroenterology
Pisa University Hospital
2
Dig Liver Dis. 2013 Sep;45(9):776-81.
3
Report of 2 cases
4
1 Department of Diagnostic and Interventional Radiology, Pisa, Italy 2 Department of Gastroenterology, Pisa, Italy
3 Department of Oncology, Pisa, Italy
Rodolfo Sacco2, Alessandra Scionti1, Valeria Mismas2, Gianluca Masi3, Caterina Vivaldi3, Carlo
Bartolozzi1, Irene Bargellini1
IDENTIFICATION OF RESPONDERS TO
SORAFENIB IN HEPATOCELLULAR CARCINOMA:
IS TUMOR VOLUME MEASUREMENT THE WAY
FORWARD?
Oncology. 2014;86(4):191-8.
5
Survival of patients based on tumor
volume ratio
65,9%
Volume ratio ≤1,17
Volume ratio >1,17
90 %
40 %
One-year cumulative survival rate
Overall survival
6
RECIST / mRECIST /EASL: Stable Disease;
V ratio = 2,21; survival 5,5 months; progressive disease
Pre
2 months
V = 23cc3
V = 51cc3
Oncology. 2014;86(4):191-8.
7
Molecular analysisof cell-free
circulat ing DNA for the
diagnosis of somatic mutat ions
associated with resistance to
tyrosine kinase inhibitors in
non-small-cell lung cancerExpert Rev. Mol. Diagn. Early online, 1–16 (2014)
Marzia Del Re1,
Enrico Vasile2,
Alf redo Falcone2,
Romano Danesi* 1 and
Iacopo Petrini2
1Department of Clinical and
Experimental Medicine, Clinical
Pharmacology Unit, Pisa University,
Pisa, Italy2Department of Translational Research
and New Technologies in Medicine and
Surgery, Medical Oncology Unit,
Pisa University, Pisa, Italy
Author for correspondence:
Tel.: +39 050 992 632
In non-small-cell lung cancer, the molecular diagnosis of somatic mutations is instrumental for
the choice of the most appropriate treatment. However, despite an initial response, resistance
to tyrosine kinase inhibitors occurs and thereafter tumors progress. For this reason, next
generation inhibitors able to overcome acquired resistances are currently in development.
Therefore, the identification of the molecular determinants of resistance is needed to adapt
treatment accordingly. The analysis of circulating cell-free tumor DNA represents a powerful
tool to monitor the somatic changes induced by treatment. This review focuses on the most
recent advantages in the diagnosis of acquired resistance in circulating cell-free tumor DNA
and underlines the strategies ready to be translated in the clinical practice.
KEYWORDS: acquired resistance • ALK • circulating cell-free tumor DNA • EGFR • non-small-cell lung cancer
• pharmacologic inhibitors
Non-small-cell lung cancer (NSCLC) is the
worldwide leading cause of death for neoplastic
diseases. Surgery is themainstay of treatment in
stages I and II (25–30% of new diagnosis) with
5-year survival rates of 60–80% and 40–50%,
respectively [1]. For advanced diseases, the only
option isasystemic treatment including chemo-
therapy or molecularly targeted drugs. The his-
tology of the NSCLC (FIGURE 1A) (squamous cell
vs adenocarcinoma) and the presence of onco-
genic mutations determine the choice of treat-
ment. Indeed, different types of oncogenic
drivers seem to characterize tumors with differ-
ent histologies [2,3]. For adenocarcinomas, the
identification of mutations already influences
thestandard clinical care.
Mainly, two different approaches have been
adopted to study the mutations of NSCLC;
the first one attempts to identify mutations in
already defined cancer genes (proto-oncogenes
and tumor-suppressor genes); the second one
screens the entire genome for mutations using
next-generation sequencing and then tries to
define which mutations are relevant for the
cancer growth.
In adenocarcinomas, using a combination
of whole-genome and exome sequencing, the
median exomic mutation rate was one of the
highest observed to date (8.1 events/mega-
base) [2]. Therefore, ‘driver’ mutations, those
able to guide the tumor growth, are diluted
within a large number of ‘passenger’ muta-
tions. These ‘passenger’ mutations occur ran-
domly and, in highly replicative tumor cells,
are determined by the intrinsic error of the
DNA polymerase and by the defective DNA
repair mechanisms. The statistically recurrent
somatic mutationsare the candidate driversof
tumor growth, and those identified using
exome sequencing are summarized in FIGURE 1B.
This list includes most of the genes that are
possible targetsof therapy and geneswithout a
developed inhibitor known to be relevant for
adenocarcinomas’ biology including KRAS,
informahealthcare.com 10.1586/14737159.2014.908120 Ó 2014 Informa UK Ltd ISSN 1473-7159 1
Review
Ex
pert
Rev
iew
of
Mo
lecula
r D
iag
no
sti
cs D
ow
nlo
aded
fro
m i
nfo
rmah
ealt
hcare
.co
m b
y 2
.19
9.4
3.1
10
on
04
/12
/14
Fo
r p
ers
on
al
use o
nly
.
Molecular analysis of cell-f ree
circulat ing DNA for the
diagnosis of somatic mutat ions
associated with resistance to
tyrosine kinase inhibitors in
non-small-cell lung cancerExpert Rev. Mol. Diagn. Early online, 1–16 (2014)
Marzia Del Re1,
Enrico Vasile2,
Alf redo Falcone2,
Romano Danesi* 1 and
Iacopo Petrini2
1Department of Clinical and
Experimental Medicine, Clinical
Pharmacology Unit, Pisa University,
Pisa, Italy2Department of Translational Research
and New Technologies in Medicine and
Surgery, Medical Oncology Unit,
Pisa University, Pisa, Italy
Author for correspondence:
Tel.: +39 050 992 632
In non-small-cell lung cancer, the molecular diagnosis of somatic mutations is instrumental for
the choice of the most appropriate treatment. However, despite an initial response, resistance
to tyrosine kinase inhibitors occurs and thereafter tumors progress. For this reason, next
generation inhibitors able to overcome acquired resistances are currently in development.
Therefore, the identification of the molecular determinants of resistance is needed to adapt
treatment accordingly. The analysis of circulating cell-free tumor DNA represents a powerful
tool to monitor the somatic changes induced by treatment. This review focuses on the most
recent advantages in the diagnosis of acquired resistance in circulating cell-free tumor DNA
and underlines the strategies ready to be translated in the clinical practice.
KEYWORDS: acquired resistance • ALK • circulating cell-free tumor DNA • EGFR • non-small-cell lung cancer
• pharmacologic inhibitors
Non-small-cell lung cancer (NSCLC) is the
worldwide leading cause of death for neoplastic
diseases. Surgery isthemainstay of treatment in
stagesI and II (25–30% of new diagnosis) with
5-year survival rates of 60–80% and 40–50%,
respectively [1]. For advanced diseases, the only
option isasystemic treatment including chemo-
therapy or molecularly targeted drugs. The his-
tology of the NSCLC (FIGURE 1A) (squamous cell
vs adenocarcinoma) and the presence of onco-
genic mutations determine the choice of treat-
ment. Indeed, different types of oncogenic
drivers seem to characterize tumors with differ-
ent histologies [2,3]. For adenocarcinomas, the
identification of mutations already influences
thestandard clinical care.
Mainly, two different approaches have been
adopted to study the mutations of NSCLC;
the first one attempts to identify mutations in
already defined cancer genes (proto-oncogenes
and tumor-suppressor genes); the second one
screens the entire genome for mutations using
next-generation sequencing and then tries to
define which mutations are relevant for the
cancer growth.
In adenocarcinomas, using a combination
of whole-genome and exome sequencing, the
median exomic mutation rate was one of the
highest observed to date (8.1 events/mega-
base) [2]. Therefore, ‘driver’ mutations, those
able to guide the tumor growth, are diluted
within a large number of ‘passenger’ muta-
tions. These ‘passenger’ mutations occur ran-
domly and, in highly replicative tumor cells,
are determined by the intrinsic error of the
DNA polymerase and by the defective DNA
repair mechanisms. The statistically recurrent
somatic mutationsare the candidate driversof
tumor growth, and those identified using
exome sequencing are summarized in FIGURE 1B.
This list includes most of the genes that are
possible targetsof therapy and geneswithout a
developed inhibitor known to be relevant for
adenocarcinomas’ biology including KRAS,
informahealthcare.com 10.1586/14737159.2014.908120 Ó 2014 Informa UK Ltd ISSN 1473-7159 1
Review
Expert
Rev
iew
of
Mo
lecula
r D
iag
no
stic
s D
ow
nlo
ad
ed f
rom
in
form
ah
ealt
hcare
.com
by
2.1
99
.43
.11
0 o
n 0
4/1
2/1
4F
or
pers
on
al
use
on
ly.
8
The evolutionary model of drug-induced
tumor resistance
9
Mutation of KRAS in circulating DNA
after gefitinib treatment
Mutant allele
Wild-type allele
Del Re M et al., unpublished
10
Mutation of KRAS in circulating DNA
after erlotinib treatment
Mutant allele
Wild type allele
Del Re M et al., unpublished
11
Conclusions
• In patients with advanced HCC under sorafenib therapy,
MTT prolongation at pCT follow-up can be used as a mar-
ker of treatment response.
• Baseline MTT could predict treatment response in patients
candidate to sorafenib therapy.
• Tumor volume measurements are reproducible and should
be considered as an alternative to RECIST, mRECIST and/or
EASL since they may provide an early prognostic marker of
response in HCC patients.
• “Liquid biopsy” is an opportunity to monitor the clinical
evolution of cancer and allows the optimization of therapy
by adapting treatment to the molecular evolution of the
disease.
• KRAS mutation is associated with resistance to TKI and is
an important diagnostic marker.