• The diagnosis of cancer has undergone a
paradigm shift. No longer is cancer diagnosed
only based on morphological parameters. More
and more the diagnostic algorithm is supported
by immunohistochemical and molecular
alterations at the DNA, mRNAs, miRNAs and
proteomic level. Multiple platforms and high
throughput technological advances enable faster
and cheaper analysis of all these as well as the
• Liquid biopsy has the potential to provide
information about cancers without invasive
biopsy, using circulating biomarkers. These
include proteins, RNA and DNA. They can be
used in detection, diagnosis, monitoring and
detection of recurrence. While protein-based
tumour markers have been used in routine
pathology for many years, the ability to detect
mutations in circulating DNA is relatively new,
and poised to enter clinical practice.
• Almost 150 years ago, T.R. Ashworth first described
the presence of epithelial cells in the blood of a
woman with metastatic breast cancer that were similar
in appearance to her primary tumor cells. Indeed,
many patients with a variety of solid tumors, including
breast cancer, have detectable cancer cells circulating
in the bloodstream, so-called circulating tumor cells
(CTCs). CTCs represent a rare cell population in the
blood, typically less than 10 cells/mL compared with 1
million WBCs/mL. However, the detection of CTCs
within a routine blood specimen provides an
opportunity to monitor cancer noninvasively, in
essence a liquid biopsy.
– Archives et manuscrits de la Bibliothèque de
l’Académie nationale de médecine
• Archives organiques de l’Académie de médecine
– Prix de l'Académie
» Acad. Med. - Prix - Buignet Prix Buignet
» n° 1. Mandel, P. Ensemble de travaux.
• Métais, P. ; Mandel, P., « Les acides nucléiques
du plasma sanguin chez l’Homme », Comptes
rendus des séances de la Société de biologie,
20 décembre 1947, Tome CXLII, p. 241 sq
• Exosomes are actively released vesicles
(carrying RNA, DNA and protein) and can
function as inter-cellular messengers.
• Three main approaches are being
pursued: analysing circulating tumour
DNA, examining whole tumour cells in the
bloodstream and capturing small vesicles
called exosomes that are ejected by
tumours . And scientists have found that
blood platelets(RNA) might be able to offer
up cancer clues, too.
• Recent scientific advances in understanding
circulating tumor cells, cell-free DNA/RNA, and
exosomes in blood have laid a solid foundation for the
development of routine molecular ‘liquid biopsies’.
This approach provides non-invasive access to
genetic information – somatic mutations, epigenetic
changes, and differential expression – about the
physiological conditions of our body and diseases. It
opens a valuable avenue for cancer screening and
monitoring. With the rapid development of highly
sensitive and accurate technologies such as next-
generation sequencing, molecular ‘liquid biopsies’ will
quickly become a central piece in the future of
• LIQUID BIOPSIES ARE NON-INVASIVE
BLOOD TESTS THAT DETECT
CIRCULATING TUMOUR CELLS (CTCS)
AND FRAGMENTS OF TUMOUR DNA
THAT ARE SHED INTO THE BLOOD
FROM THE PRIMARY TUMOUR AND
FROM METASTATIC SITES
CANCER AND SOMATIC
• The majority of cancers arise after a series of
somatic gene mutations that accumulate during
an individual’s lifetime
• Identifying and understanding the somatic
alterations in an individual’s tumor can be crucial
in cancer diagnosis and in planning personalized
cancer treatment, monitoring response to
therapy, and identifying cancer recurrence.
Moreover, as a tumor progresses, it continues to
acquire additional alterations that can affect the
response to therapeutic agents such as
chemotherapy or targeted therapies.
• Distant metastases harbor unique genomic
characteristics not detectable in the
corresponding primary tumor of the same patient
and metastases located at different sites show a
considerable intrapatient heterogeneity. Thus,
the mere analysis of the resected primary tumor
alone (current standard practice in oncology) or,
if possible, even reevaluation of tumor
characteristics based on the biopsy of the most
accessible metastasis may not reveal sufficient
information for treatment decisions
Novel diagnostic biomarkers used in the
clinic for various types of cancers and their
targeted drug therapy.
WHAT IS A LIQUID BIOPSY?
• The term “liquid biopsy” describes non-invasive,
highly sensitive and cost effective methods of
isolating and detecting these cfDNA fragments,
including circulating tumor DNA (ctDNA), from
the plasma from patients diagnosed with cancer
or from individuals who may have cancer. Liquid
biopsies are thought to capture the entire tumor
genome When liquid biopsy techniques are
combined with deep sequencing technologies, a
new set of tools is created that identify somatic
genomic alterations in tumors.
Molecular diagnostic schema representing
routine biological specimens and their
POTENTIAL INDICATIONS FOR
• Monitor residual disease in patients with known mutations in the
• · Monitor treatment efficacy in patients.
• · Monitor disease progression and tumor evolution (i.e. development
of tumor resistance).
• · Help the physician explore other options of treatment when the
patient is resistant to current therapies.
• · Provide an alternative method for biopsy when tissue is difficult to
obtain or not available, or when the primary site of metastatic
disease is unknown.
• · Provide an alternative method for biopsy when the quantity of
tissue obtained in a biopsy sample is limited and traditional
molecular genotyping is requested.
• · Provide prognostic information for some patients.
Is this the end of tissue biopsies?
“Tissue biopsy will remain the gold standard
for the next couple of years. As scientific
knowledge advances, researchers are
learning more about the potential of liquid
biopsies to detect mutations.
• At the moment, liquid biopsies are
recommended when a tissue biopsy is
difficult, such as in the case of lung
cancer, or when the original site of the
disease is unknown.
Liquid biopsies have a powerful role in
helping patients get to the right treatment.
• Molecular analysis of cancer is required to
optimise patient treatment
• New methods such as next generation
sequencing show immense promise for the
• Liquid biopsy is coming of age and will
change practice – it will enable oncologists
to use drugs intelligently to combat
changes in individual cancers as they