351cascades, mediators of acquired resistance must be elucidated for each disease
separately in the context of treatment.
Patients with EGFRm + NSCLC are particularly sensitive to treatment with cur-
rently available EGFR TKIs, which block the cell signaling pathways that drive the
growth of tumor cells. However, tumor cells almost always develop resistance to
treatment, leading to disease progression. In approximately half of patients, this
resistance is caused by the secondary mutation known as T790M. AZD9291
(AstraZeneca) is a highly selective, irreversible inhibitor of both the activating sen-
sitizing EGFR mutation (EGFRm+) and the activating resistance mutation, T790M,
while sparing the activity of wild type EGFR. There are currently no targeted thera-
pies approved for the treatment of tumors with this resistance mutation. In the ongo-
ing phase I study, AZD9291 has shown early evidence of activity as a once-daily
monotherapy with clinical responses observed in an EGFRm + population of patients
with NSCLC who have previously failed on EGFR TKIs and also in patients with
the T790M mutation. AZD9291 has been well-tolerated with low rates of side
effects. AstraZeneca is collaborating with Roche to develop a plasma-based com-
panion diagnostic test for EGFR mutations in both tumor tissue and plasma derived
from patients with NSCLC, and to optimize the clinical development of AZD9291.
Molecular Subtyping of Lung Cancer
Lung adenocarcinoma (LAD) has extreme genetic variation among patients, which
is not well understood and limits progress in research and development of therapy.
LAD molecular subtypes are a validated stratifi cation of naturally-occurring gene
expression patterns and encompass different functional pathways and patient out-
comes. Different subtypes may be the result of mutations and alterations in gene
expression. LAD molecular subtypes (bronchioid, magnoid, and squamoid) were
tested for association with gene mutations and CNVs using statistical methods and
published cohorts (Wilkerson et al. 2012 ). A novel validation cohort was assayed
and interrogated to confi rm subtype-alteration associations. Mutation rates of genes
(EGFR, KRAS, STK11, and TP53), chromosomal instability, regional copy num-
ber, and genome wide DNA methylation were signifi cantly different among tumors
of the molecular subtypes. Secondary analyses compared subtypes by integrated
alterations and patient outcomes. Tumors having integrated alterations in the same
gene associated with the subtypes, e.g. mutation, deletion and underexpression of
STK11 with magnoid, and mutation, amplifi cation, and overexpression of EGFR
with bronchioid. The subtypes also associated with tumors having concurrent
mutant genes, such as KRAS-STK11 with Magnoid. Overall survival of patients,
cisplatin plus vinorelbine therapy response, and predicted gefi tinib sensitivity were
signifi cantly different among the subtypes. The study concluded that LAD intrinsic
molecular subtypes co-occur with grossly distinct genomic alterations that affect
response to therapy. These results advance the understanding of etiology of LAD
and help in selection of patient subgroups for future evaluation of treatment response.
Lung Subtype Platform (LSP™) is being developed commercially by GeneCentric.
Personalized Management of Cancers of Various Organs