Personalized Health Care (PHC) in Cancer - Genomic Biomarkers for Pharmaceutical Development - page 35

levels of the active metabolite endoxifen or genotype the rarer CYP2D6 alleles [87-89] , mak-
ing it difficult to fully interpret these results.
In 2006, an FDA advisory panel recommended adding a warning to tamoxifen indicating
that CYP2D6 genotyping is an option for women with BC being considered for this treat-
ment, although the ASCO guidelines recommended against it at the time [90] . Furthermore,
multiple retrospective analyses support the use of CYP2D6 genotype to guide the dose and
selection of tamoxifen, but this testing has yet to be made mandatory. If the predictive abil-
ity of CYP2D6 genotyping results is confirmed in a prospective trial, this evaluation may
become routine for ER+ patients in order to identify those who should consider alternative
therapies to block activation of the ER, such as aromatase inhibitors.

2.2.3 Prognostic Biomarkers
Prognostic biomarkers differentiate between cancer patients likely to have different out-
comes and may determine what therapy is utilized, as well as define the course of treatment.
General examples of prognostic biomarkers utilized across multiple cancer indications include
cancer stage, tumor grade, and existence of distant metastases. A more specific example exists
in CRC where stage, grade, and extent of vascular invasion are used in combination to describe
a subgroup of stage II colon cancer patients who may have improved potential for survival
from adjuvant chemotherapy [91] . Recently, molecularly-based tests have emerged as prognos-
tic biomarkers, particularly for breast cancer patients [92,93] , but for other indications as well.
Oncotype DX (Genomic Health) is a 21-gene transcript-based assay indicating the probabil-
ity of BC recurring after surgical intervention [94-97] . This test was developed specifically as a
prognostic test to assess the benefit of chemotherapy in women with node-negative, ER+ breast
cancer who have been treated with tamoxifen, as well as identifying patients at greatest risk of
relapse following treatment [94-97] . To develop this test, a real-time PCR method was used in
FFPE tumor samples to quantify expression of 250 candidate genes selected from the literature
based on data from fresh-frozen tissue [98] . Three independent studies comprising a total of
447 patients were used to evaluate the relationship between the candidate genes and BC recur-
rence. Based on these studies the expression of a panel of 16 cancer-related genes and five ref-
erence genes was used to calculate a recurrence score for each tumor sample [98] . Figure 2.4

FIGURE 2.4

21-gene panel used to calculate recur-

Proliferation
Ki67
STK15
Survivin
CCNB1
MYBL2

Estrogen
ER
PR
BCL2
SCUBE2

Reference
ACTB
GAPDH
RPLPO
GUS
TFRC

rence score [98] .

Invasion
MMP11
CTSL2

HER2
GRB7
HER2

Other
GSTM1
CD68
BAG1