Personalized Health Care (PHC) in Cancer - Genomic Biomarkers for Pharmaceutical Development - page 37

patients with 0-3 positive nodes for adjuvant chemotherapy [106] . Although complex, the
study aims to address whether low risk patients defined by MammaPrint have good prog-
nosis when treated with endocrine therapy only, and if patients identified as high risk by
pathological parameters but low risk by MammaPrint (about 10-15% of participants) have
good prognosis when treated with endocrine therapy only [106] . The I-SPY 2 trial is an addi-
tional study examining MammaPrint [107] , and this is using an adaptive design to iden-
tify improved treatment regimens for patients grouped by particular molecular signatures
[107] . In this trial, standard biomarkers such as hormone receptor status, HER2 status, and
MammaPrint status are used to assign various treatments and randomize patients to one
of five drugs added to standard neoadjuvant chemotherapy [107] . Many of the biomarker
signatures evaluated in this trial represent disease areas where there is need for improved
treatment, such as hormone receptor and HER2 negative tumors and tumors with poor
prognosis based on high MammaPrint scores. Trials utilizing an adaptive design with multi-
ple drugs provide important platforms for the evaluation of numerous biomarker strategies
that may be important for the success of new therapeutics.
2.2.4 Resistance Biomarkers
It is often the case that cancer therapies work for a period of time, but then tumors
develop resistance to a particular therapy, often in a majority of the patients. Although there
are currently no FDA approved resistance biomarkers for use with specific drugs, many are
being investigated and showing promise. For EGFR TKIs, one resistance mechanism involves
secondary mutations in EGFR, where the best studied is EGFR T790M in exon 20, found in
approximately 50% of patients with acquired resistance [108-110] . This mutation in EGFR
can also be detected in plasma, making it possible that circulating EGFR T790M could be
used in the early detection of resistance [111] and to identify patients in need of alternative
therapeutics.
Resistance to imatinib occurs in about 10-15% of CML patients, often due to mutations
in the catalytic domain of the BCR-ABL fusion protein [112] . With this knowledge of resist-
ance mechanisms to imatinib, other drugs have been identified to work in imatinib-resistant
CML, such as dasatinib and nilotinib [113-116] . Both of these TKIs have activity against other
kinases, which may help explain their efficacy in this setting [113-116] . Molecular analyses
have been utilized to screen for catalytic domain mutations in BCR-ABL that might play a
role in resistance, which could ultimately be used to select alternative treatments to imatinib
for patients likely to develop resistance.
2.2.5 Surrogate Biomarkers
A biomarker can also serve as a surrogate endpoint when it is used to substitute for an
established clinical endpoint. To be a direct substitute for a clinical benefit endpoint, a sur-
rogate endpoint must be correlated with the clinical outcome and must fully capture the net
effect of treatment on the clinical outcome. One example of this principle is that a drug that
lowers low density lipoprotein (LDL) can be approved by the FDA on that basis alone with-
out the requirement for direct clinical evidence of the reduction of risk of cardiovascular dis-
ease. The benefit of reduced LDL on cardiovascular risk is so well established that reduction