world cancer report - iarc

THE MOLECULAR DETECTION OF
MINIMAL RESIDUAL DISEASE
The accurate identification of submicroscopic
numbers of residual cancer cells
has important clinical implications for
many malignancies. Treatment efficacy is
frequently monitored by the disappearance
of tumour cells from the blood or
bone marrow, and while microscopic
examination of marrow is extremely valuable,
it is a relatively insensitive tool for
the detection of this “minimal residual
disease”. Much effort has therefore been
directed towards the development of sensitive
and specific molecular assays of
minimal residual disease with the main
molecular strategy involving the use of
the polymerase chain reaction (PCR) technique.
Since its inception in 1985, this
technique has been widely utilized as a
means of amplifying (i.e. repeatedly copying)
target DNA sequences up to a millionfold
with great specificity, due to the use
of oligonucleotide primers unique to the
sequence of interest (Saiki RK et al.,
Science, 230: 1350-54, 1985). Numerous
studies have reported the use of PCRbased
techniques for detecting minimal
residual disease in a range of cancers
including leukaemia, lymphoma, breast
cancer, prostate cancer and melanoma.
Detection limits of one cancer cell
Fig. 5.117 A biopsy section from a patient with
chronic myelogenous leukaemia, myeloid blast
phase. Sheets of abnormal megakaryocytes, including
micromegakaryocytes, are illustrated. Blasts
infiltrate between the abnormal megakaryocytes.
246 Human cancers by organ site
amongst 10 4-10 6 normal cells can routinely
be achieved, a level of sensitivity that is
some 3 to 5 orders of magnitude more sensitive
than conventional techniques. PCR
can, therefore, serve as an ultrasensitive
tool for accurately identifying small numbers
of cancer cells in patient samples.
The potential clinical utility of minimal
residual disease detection for both
haematopoietic malignancies and solid
tumours has been demonstrated in a range
of studies. For example, there is now
strong evidence that the level of minimal
residual disease measured in the first few
months of therapy in children undergoing
treatment for acute lymphoblastic
leukaemia is highly prognostic of outcome
(Cave H et al., New Engl J Med, 339: 591-8,
1998; van Dongen JJM et al., Lancet,
352:1731-8, 1998). These studies have utilized
clone-specific rearrangements of antigen
receptor genes as the targets for PCR
amplification of genomic DNA. Other studies,
particularly those involving solid
tumours, have relied on reverse transcriptase
(RT-PCR) amplification of cancer-specific
messenger RNA as an indicator of the
presence of residual disease. While these
RT-PCR techniques offer valuable clinical
information, especially in tumour staging,
there is currently enormous variability
when comparing inter-laboratory assays.
Such ultrasensitive methods can be
sis die of infection or, less commonly,
bleeding. Large gains in survival in acute
myeloid leukaemia have come with the
introduction of improved supportive care
and combination chemotherapy. Effective
drugs include cytarabine, anthracyclines,
etoposide, mitoxantrone, amsacrine, 6thioguanine
and 5-azacytidine. Intensive
therapy is applied until a complete remission
is achieved with