265contain the MLL-AF4 or the BCR-ABL fusion are often candidates for allogeneic
hematopoietic stem cell transplantation during fi rst remission. Patients with acute
promyelocytic leukemia who carry the PML-RAR alpha fusion respond to all-trans
retinoic acid and have an excellent outcome after treatment with all-trans retinoic
acid in combination with anthracyclines.
Testing Microsatellite-Instability for Response to Chemotherapy
Microsatellites are stretches of DNA in which a short motif (usually one to fi ve
nucleotides long) is repeated several times. Microsatellite instability occurs when a
germ-line microsatellite allele has gained or lost repeat units and has thus under-
gone a somatic change in length. Because this type of alteration can be detected
only if many cells are affected by the same change, it is an indicator of the clonal
expansion, which is typical of a neoplasm.
To test for microsatellite instability, DNA from the tumor and from normal tissue
(blood, a buccal smear, or normal colonic mucosa) is tested by genotyping fl uores-
cently labeled PCR products with the use of an automated sequencer. A panel of fi ve
microsatellite markers is usually adequate with microsatellite instability in two or
more of them indicate a positive result. Such tests could help physicians determine
a patient’s prognosis and serve as a guide to therapy.
Fluorouracil-based adjuvant chemotherapy benefi ts patients with stage II or
stage III colon cancer with microsatellite-stable tumors or tumors exhibiting low-
frequency microsatellite instability but not those with tumors exhibiting high-
frequency microsatellite instability. Although the results in vitro studies suggest
that fl uorouracil-based adjuvant chemotherapy is not benefi cial in patients with
colon cancer exhibiting high-frequency microsatellite instability, other drugs, such
as the topoisomerase-I inhibitor camptothecin, have been shown to kill mismatch-
repair- defi cient cancer cells exhibiting high-frequency microsatellite instability.
Therefore, it would be important to conduct molecular analyses of specimens from
recent clinical trials of non-fl uorouracil-based chemotherapies and to ensure that
future trials include analyses of molecular pathways. In this retrospective analysis,
the fi nding that fl uorouracil-based adjuvant chemotherapy does not signifi cantly
increase, and may potentially decrease, overall and disease-free survival among
patients with tumors exhibiting high-frequency microsatellite instability raises
several provocative issues regarding postoperative management of stage II and
stage III colon cancer. Currently available evidence is not strong enough for
decision- making in clinical practice. However, these fi ndings, if confi rmed by
other analyses of previous, well-designed clinical trials or by future prospective,
randomized, controlled studies, indicate that microsatellite-instability testing
should be conducted routinely and the results used to direct rational adjuvant che-
motherapy in colon cancer.
Pharmacogenomic-Based Chemotherapy