307chemotherapy in some breast cancer patients, scientists at Dana-Farber Cancer
Institute (Boston, MA) scanned the genome of stored breast cancer samples from
patients who had been treated according to modern guidelines, including the use of
anthracyclines. Use of integrated genomics enabled identifi cation of a small number
of overexpressed and amplifi ed genes from chromosome 8q22 that are associated
with early disease recurrence despite anthracycline-based adjuvant chemotherapy
(Li et al. 2010 ). The association was confi rmed in an analysis of multiple indepen-
dent cohorts. SiRNA-mediated knockdown of either of two of these genes, the anti-
apoptotic gene YWHAZ and a lysosomal gene LAPTM4B, sensitized tumor cells to
anthracyclines, and overexpression of either of the genes induced anthracycline
resistance. Overexpression of LAPTM4B resulted in sequestration of the anthracy-
cline doxorubicin, delaying its appearance in the nucleus. Overexpression of these
two genes was associated with poor tumor response to anthracycline treatment in a
neoadjuvant chemotherapy trial in women with primary breast cancer. These results
suggest that 8q22 amplifi cation and overexpression of LAPTM4B and YWHAZ
contribute to de novo chemoresistance to anthracyclines and allow metastatic recur-
rence. Overexpression of these two genes may predict anthracycline resistance and
infl uence selection of chemotherapy. These fi ndings could lead to a genetic test of
breast cancers to help physicians choose the best initial treatment for an individual
patient that is less likely to lead to development of resistance. Such a test should not
be diffi cult to develop and could be available for clinical testing in the near future.
Testing prior to start of chemotherapy would help to personalize the treatment and
reduce the possibility of development of resistance.
The 78-kDa glucose-regulated protein (GRP78), widely used as an indicator of
the unfolded protein response (UPR), is induced in the tumor microenvironment. In
vitro studies suggest that GRP78 confers chemoresistance to topoisomerase inhibi-
tors, such as Adriamycin (doxorubicin) used for the treatment of breast cancer. In a
retrospective study of breast cancer patients who were treated with Adriamycin,
archival tumor specimens were analyzed and the relationship of GRP78 expression
level to “time to recurrence” (TTR), used as a surrogate biomarker for drug resis-
tance, was examined (Lee et al. 2006 ). The data show that 67 % of the study sub-
jects expressed high level of GRP78 in their tumors before the initiation of
chemotherapy and suggest an association between GRP78 positivity and shorter
time to recurrence. The use of GRP78 as a predictor for chemoresponsiveness and
the potential interaction of GRP78 and/or the UPR pathways with taxanes warrant
larger studies.
An experimentally derived IFN-related DNA damage resistance signature
(IRDS) is associated with resistance to chemotherapy and/or radiation across differ-
ent cancer cell lines (Weichselbaum et al. 2008 ). The IRDS genes STAT1, ISG15,
and IFIT1 all mediate experimental resistance. Clinical analyses reveal that IRDS +
and IRDS − states exist among common human cancers. In breast cancer, a seven
gene-pair classifi er predicts for effi cacy of adjuvant chemotherapy and for local-
regional control after radiation. By providing information on treatment sensitivity
or resistance, the IRDS improves outcome prediction when combined with standard
markers, risk groups, or other genomic classifi ers.
Personalized Management of Cancers of Various Organs