Personalized Health Care (PHC) in Cancer - Genomic Biomarkers for Pharmaceutical Development - page 25

Patients receiving any endocrine therapy (n = 777)

1.0

IHC Score (% patients)

8 (5.8%)
7 (19.8%)
5 (17.4%)
6 (23.4%)
4 (11.7%)
3 (5.1%)
2 (2.1%)
0 (14.7%)

0.8

ER positive

0.6

ER negative

0.4

0.2 Best Cutpoint: IHC score > 2 (p<0.0001)

0.0

0 12 24 36

Time (months)

48 60 72

FIGURE 2.1 Comparison of disease-free survival curves for all possible Allred IHC scores for ER staining used
to determine cutoff score distinguishing a positive from a negative result [8] . ER positivity is indicated by an Allred
score ≥3 (indicating >1% of cells with weak staining).

utilized 194 randomized trials where patients received adjuvant chemotherapy and tamox-
ifen, and showed that tamoxifen reduced the 15-year breast cancer recurrence rate from 45%
to 33% and reduced BC mortality by 35% in ER+ patients, but was ineffective in ER− patients
[11] . Based on these data and others, the use of tamoxifen as hormonal therapy is currently the
standard of care in breast cancer, especially in premenopausal women. Other therapies that
inhibit the ER exist, such as aromatase inhibitors, which prevent the conversion of androgens
to estrogens, causing a reduction in estradiol levels [6] . Regardless of the estrogen-modulating
therapy, clear responses are only seen in patients who meet the criteria for ER positivity.
Despite the benefits observed following tamoxifen and other hormonal therapies, addi-
tional work needs to be done to identify patients likely to respond to treatments that inhibit
ER function. The negative predictive value (NPV) of ER expression is high, meaning that
ER-negative patients almost never benefit from hormone therapy; however, the positive-
predictive value (PPV) of ER expression is lower, in that only about 50% of ER+ patients
respond to hormone therapy [11-13] . Additionally, approximately 33% of cancers treated
with adjuvant hormonal therapy will recur [6] , and there are currently no tests to prospec-
tively identify which ER+ patients will ultimately respond or develop resistance to endocrine
therapy. The development of additional biomarkers to be used in combination with ER status
to identify patients more likely to respond to anti-estrogen therapy hopefully will be the next
step in the evolution of the treatment of ER+ cancer.

HERCEPTIN / TRASTUZUMAB FOR BREAST CANCER
HER2 (also known as ErbB2) is a member of the epidermal growth factor receptor family,
which regulates key cellular pathways, including proliferation, migration, and adhesion [14] .
HER2 is overexpressed in approximately 25% of breast tumors, leading to poorer prognosis