La biopsia liquida dei tumori: il viaggio
Paola Gazzaniga
Liquid Biopsy Unit Dept. Molecular Medicine Sapienza University of Rome
Must Know Necessary Travel Tips
“There is lack of drugs to treat all the gene variants identified through next-generation sequencing of cell-free DNA. The
challenge is, what do we do with all the information?
“I would trust the prospective trial more than a retrospective database analysis. Too many retrospective studies.
This is a bizarre way to proceed“
“not even been demonstrated that liquid biopsies improve
outcomes in patients with different types of metastatic disease, much less in undiagnosed individuals.“
Intratumor heterogeneity Clonal evolution of cancer
1) Point of departure
Tissue sampling bias
Tumor heterogeneity exists and cancer researchers , pathologists
and oncologists ignore heterogeneity at their own peril.
Can we use a liquid biopsy to overcome single biopsy bias?
2) A destination
3) Mode of transport
Which liquid biopsy?
Gold et al, J. Mol Diagn,17: 209-224, 2015
Evidence level I
(mts breast
mts colon and prostate)
III II
I
preclinical
3) Mode of transport
Which liquid biopsy?
4) The baggage
1. Concordance tissue/plasma
:the case of lung cancer
On June 1, 2016, the U. S. Food and Drug Administration approved Cobas EGFR Mutation Test v2 (Roche Molecular Systems, Inc.) using plasma specimens as a companion diagnostic test for the detection of exon 19 deletions or exon 21 (L858R) substitution mutations in the epidermal growth factor receptor (EGFR) gene to identify patients with metastatic non-small cell lung cancer (NSCLC) eligible for treatment with erlotinib
The concordance rate between ctDNA and the tumor was 87%, with sensitivity of 76.7% and specificity of 98%.
Patients with positive cobas® EGFR Mutation Test v2 test results using plasma specimens for the presence of EGFR exon 19 deletions or L858R mutations are eligible for treatment with erlotinib
Patients who are negative for these mutations by this test should be reflexed to routine biopsy and testing for EGFR mutations with the FFPET sample type.
1. Concordance tissue/plasma:
the case of colorectal cancer
Overall agreement (concordance) was 90%
The high concordance of plasma and tissue results demonstrates that blood-based RAS mutation testing is a
viable alternative to tissue- based RAS testing
Grasselli J et al, Ann Oncol. 2017 Jun 1;28(6):1294-1301
The baggage
Progression-free survival after anti-EGFR plus irinotecan-based therapy is the same for tissue wtRAS and plasma wtRAS
Grasselli J et al, Ann Oncol. 2017 Jun 1;28(6):1294-1301
Much more mutations were found by ctDNA analysis: 59%, 11.8% and 14.4% of the patients were found KRAS, NRAS and BRAF mutant by ctDNA analysis instead of 44%, 8.8% and 7.2% by tumor-tissue
analysis.
Altogether, the clinical data with respect to the anti-epidermal growth factor receptor response of those discordant patients do not appear contradictory to the
mutational status as determined by plasma analysis.
Thierry AR et al, Ann. Oncol, 2017 ; 28: 2149-59 Our assay is not intended to compare the analytical performance of one method for plasma testing with that of one method for tissue testing, but rather to examine the value of plasma analysis versus tissue analysis under standard management care.
There is here a clear demonstration that ctDNA provides strong evidence for a more rapid data turnaround time than tumor-tissue analysis,
irrespective of the methods used.
Thierry AR et al, Ann. Oncol, 2017 ; 28: 2149-59 In comparison with tumor-tissue analysis, a blood test appears more
cost-effective for genotyping-guided clinical care.
Median tumor-tissue data turnaround-time was 16 days while 2 days for ctDNA analysis.
2. ctDNA high/low in the assessment of prognosis
Association of baseline plasma DNA concentrations with overall survival in patients
who received placebo
Tabernero J. Et al, Lancet Oncol. 2015 Aug;16(8):937-48.
3. Monitoring resistance to targeted therapy: the case of colorectal cancer
acquired resistance to EGFR‐specific antibodies is associated with the emergence of RAS pathway mutations
these mutations can be detected in the blood of colorectal cancer patients before disease progression is clinically manifest
KRAS mutated alles decline when anti-EGFR treatment is suspended.
Anti-EGFR induce a SELECTIVE PRESSURE
Siravegna et al, 2015
Clara Montagut, ESMO CRC ,Valencia, May 12, 2017
While travelling: an air-pocket
Our hand- baggage
FFPE ctDNA 1 ctDNA 2 ctDNA 3 ctDNA 4
G12C wt G12C G12C wt
Q61H Q61H wt
G12D G12D G12D
G13D G13D
G12A G12A
G12C G12C
G12C wt wt wt
G12V G12V G12V G12V
N-Ras mut wt wt
G13D G13D wt wt
G12V wt wt wt
G 12 D G12D
G12V wt wt
wt wt wt wt
wt wt wt
wt wt wt wt
wt wt
wt wt wt
wt Q61H Q61H
wt G12C G12C
wt wt wt
wt wt wt
wt wt
wt wt
wt G12D
wt wt
CT+bev
CT+anti-EGFR
7/13 (54%)
3/13 (23%)
Our hand- baggage
ctDNA might expand therapeutic options for second line treatment of KRAS mutant mCRC
Gazzaniga P et al, ESMO, Madrid, 2017
These interventional tests can now be used to guide anti-EGFR treatment in EGFR mutated non-small-cell lung cancer patients using blood when access to tissue is impaired.
EGFR mutations assays in ctDNA are the only companion diagnostic tests approved by the regulatory agencies in Europe and in the USA
5) The passport
Additional interventional studies are required to demonstrate the clinical utility of a liquid biopsy, i.e., its capacity inform to adopt or to reject a therapeutic action.
Until now, most, if not all, ctDNA-based investigations have been in essence proof-of-concept reports.
Arrival is not necessarily the final destination
6) The purpose of the journey
“The real voyage of discovery consists, not in seeking new landscapes, but in having new eyes.“
Marcel Proust
Open label, single-arm, Phase II trial.
The trial has been designed to prove or disprove whether a third line rechallenge with panitumumab can achieve an objective response rate (ORR= CR+PR) of 30% or more in a population
of RAS wild type mCRC patients selected on the basis of RAS extended clonal evolution in their plasma
The ancient Greeks had two words for time, chronos and kairos. Where chronos is
quantitative, kairos is qualitative. It measures moments, not seconds. Further, it refers to the right moment, the opportune moment. The perfect moment.
The world takes a breath, and in the pause before it exhales, fates can be changed.
mRAS wtRAS
1° line including anti-angiogenic
2° line including EGFR-inhibitors
% mut RAS
time
KAIROS
Keeping the Advantage of the Impermanent RAS-wt window Offering Second-line EGFR inhibitors
Gazzaniga P, ESMO Madrid, 2017
The purpose of the journey
19% of patients had one or more ctDNA alterations associated with an FDA-approved therapy
Finally, although target prioritization is a major stake, it must be emphasized that drug discovery, development and testing will certainly be the major bottlenecks of precision medicine.
Cristina Raimondi Chiara Nicolazzo Angela Gradilone Maria Laura Mancini
Alain Gelibter Enrico Cortesi
Alberto Sobrero
Laura Bracci
