Biology Reference
In-Depth Information
process and could be validated in prospective trials and co-developed as a companion diag-
nostic. Similarly for mutations / genetic alterations, if they exist in the drug target itself, the
opportunity for co-development of a companion diagnostic may accelerate drug approval;
however, if the genetic alteration occurs outside of the target pathway, this may only be iden-
tified through retrospective genetic analyses of responder / non-responder populations fol-
lowing completed large Phase II and Phase III trials. Finally, discovery of alterations in drug
metabolism due to a patient's genotypic background may be extremely difficult to predict
prior to large Phase III clinical trials or even prior to FDA approval due to the need for retro-
spective analyses of large patient populations to identify / validate such relationships, unless
pre-clinical work has implicated a drug-metabolizing enzyme that is inhibited or is involved
in activating or inactivating a small molecule drug.
2.2.2.1 Target / Pathway Expression
ESTROGEN RECEPTOR (ER) AND HORMONE THERAPY IN BREAST CANCER
One of the original predictive biomarkers shown to have clinical relevance is the estrogen
receptor (ER) in breast cancer (BC). In the late 1800s, Sir George Beatson reported that three
women with advanced BC experienced regression of their tumors following oophorectomy,
starting the idea that hormonal manipulation could influence BC progression [4] . Subsequent
trials demonstrated that sensitivity to hormonal manipulation was observed in tumors that
express ER alpha [5] . Once the connection between ER expression and response to hormonal
therapy had been established, it became critical to develop a method to identify ER expressing
tumors. Originally this was done using ligand binding assays; however, current practice is to
use immunohistochemistry (IHC) in formalin-fixed, paraffin embedded (FFPE) tumor blocks
to determine ER status [6] . Several systems have been devised to score results from IHC tests
of ER in breast tissue, one of which is the Allred score [7] . The Allred score provides an over-
all score of either 0 or 2-8 by summing the proportion of cells with positive staining and the
average staining intensity [7] . To determine a cutoff distinguishing ER-positive samples from
ER-negative samples, the IHC assay results were compared with clinical outcome. This com-
parison revealed that an Allred score of 3 was the lowest score predicting a positive response
to hormonal therapy ( Fig. 2.1 ) and this score corresponds to as few as 1-10% positive tumor
cells [7,8] . The American Society of Clinical Oncology (ASCO) and the College of American
Pathologists incorporated this information into specific guidelines for testing and scoring of
ER expression, such that ≥ 1% of tumor cells staining positive is considered sufficient to pre-
dict response to hormonal therapy [8] . Using the criteria of 1-10% ER expression as positive,
approximately 70% of all breast cancers qualify for hormonal therapy [8] .
Support for the hypothesis that ER levels correlate with benefit from anti-estrogen therapy
emerged in the early 1970s, in studies showing that 50% of ER+ patients with advanced BC
experienced regression following endocrine ablative therapy or hormone therapy, whereas
ER− patients rarely responded to these therapies [9] . In 1998, a meta-analysis of 55 clinical trials
comparing tamoxifen, a selective ER modulator that blocks transcription of estrogen-depend-
ent genes and inhibits breast tumor proliferation, versus placebo for the adjuvant treatment of
early invasive BC showed a 50% reduction in disease recurrence rates and a 28% reduction in
mortality rate in ER+ patients following 5 years of tamoxifen treatment, whereas little benefit
was observed in patients with ER− cancers [10] . Another recent update of this meta-analysis
Search WWH ::




Custom Search