Personalized Health Care (PHC) in Cancer - Genomic Biomarkers for Pharmaceutical Development - page 28

rapidly in nearly all patients [16,18,28] , there is certainly room for improvement in predicting
patient response to anti-HER2 therapies. Measuring other markers in addition to HER2 may
greatly increase the ability to predict response to anti-Her2 therapies like trastuzumab, which
would be of considerable benefit to patients with breast cancer.
PD-1 FOR IMMUNOTHERAPY IN MULTIPLE INDICATIONS
The programmed death-1 (PD-1) T cell co-receptor and its ligands B7-H1 / PD-L1 and
B7-DC / PD-L2 play important roles in maintaining an immunosuppressive tumor microen-
vironment. The major role of PD-1 is to limit the activity of T cells in the periphery dur-
ing an inflammatory response [30] . PD-L1 is commonly upregulated on many tumor types,
where it inhibits local T cell responses, while PD-1 is expressed on the majority of tumor-
infiltrating lymphocytes [30] . Encouraging clinical results have validated this pathway as a
target for cancer immunotherapy [31] . Clinical activity has been observed in patients with
melanoma, renal cell carcinoma, colorectal cancer (CRC), and non-small-cell lung cancer
(NSCLC) [31] . Antitumor activity of the anti-PD-1 antibody BMS-936558 was observed at
all doses tested, and in melanoma the response rates ranged from 19 to 41% in each dose
cohort. Tumor cell surface expression of the PD-1 ligand PD-L1 in pre-treatment FFPE
tumor biopsies emerged as a biomarker of response, consistent with known biology. 25 of
the 42 patients examined were positive for PD-L1 expression by IHC; of the 25 patients, 9
had an objective response (36%) compared to 0 of the 17 PD-L1 negative patients that expe-
rienced an objective response [31] . Approximately 1 in 5 individuals treated with the anti-
PD-1 antibody BMS-936558 had durable responses to the drug [31] and it is clear that the
expression of PD-L1 in tumors is a candidate predictive marker that warrants further explo-
ration for use with this promising immunotherapy.
2.2.2.2 Target / Pathway Mutation or Genetic Alteration
EGFR MAB THERAPY IN CRC
The epidermal growth factor receptor (EGFR) is frequently overexpressed and / or
mutated in cancers, including CRC, NSCLC, and glioblastoma [32-34] . Prevention of ligand
binding to this receptor inhibits signal transduction pathways such as RAS / RAF / MAPK
and PI3K / AKT cascades, which promote cell growth proliferation, invasion, and metastasis
[35] . Both monoclonal antibodies (mAbs; cetuximab and panitumumab) and small molecule
tyrosine kinase inhibitors (TKIs; gefitinib and erlotinib) are approved therapies for these
cancers [32-34,36-38] . Trials with EGFR mAbs showed responses for these agents to be
between 10 and 30% (single agent mAb and plus chemotherapy, respectively) in chemore-
fractory patients with metastatic CRC [35] . The low response rate and the poor correlation
of EGFR expression with response to anti-EGFR therapies led to the development of alterna-
tive biomarkers. KRAS is a gene involved in multiple EGFR-mediated pathways, and muta-
tions in this gene lead to constitutively activated MAPK or PI3K signaling independent of
EGFR activation. KRAS mutations occur in a large proportion of metastatic CRCs (30-50%)
and are negative prognostic factors, which supported the hypothesis that KRAS mutations
could play a role in patient response to anti-EGFR treatment [35] . Retrospective analy-
sis of several randomized clinical trials revealed that patients with mutations in the KRAS
gene rarely benefited from treatment with EGFR mAbs, making KRAS status an important