Personalized Therapy for Lung Cancer: From Lab to Clinical Application
Pan-Chyr Yang MD, PhD
National Taiwan University College of Medicine
Lung cancer is the leading cause of cancer mortality world-wide. Delayed
diagnosis, early metastasis and poor treatment outcome are the present unsolved
issues for most of the physicians who are treating the lung cancer patients. More than
75% of lung cancers patients are stage III and IV diseases at diagnosis. Recent studies
in genetic epidemiology and pharmacogenomics revealed that lung cancer in different
ethnic groups, particularly in East Asia and Chinese, is a distinct disease entity and
different from that of the Caucasian population. The PIONEER, a prospective
epidemiological study of EGFR mutations in patients from Asia with newly diagnosed,
advanced lung adenocarcinoma has confirmed that 50-55% of patients were positive
for EGFR mutations, in contrast to 10-15% positivity in Caucasian patients. The rapid
increase in non-smoker adenocarcinoma both in men and women has become an
emergent health threat to East Asia and developed countries. There is an urgent need
to develop an effective strategy for identification of the high risk patients and detect
lung cancer in earlier stage. Currently, low dose spiral CT is the most effective way to
detect small early lung cancer and my reduce lung cancer mortality. The Genetic
Epidemiology of Lung Cancer in Taiwan (GELAC) collaborated with NIH and countries in
East Asia and identified 5 specific susceptibility loci (TERT, TP63, HLA Classs II,
POS1-DCBLD1 and VTI1A) in never-smoking women in Asia. The risk gene loci
may contribute to the oncogenesis of non-smoker adenocarcinoma in East Asia
population. These SNPs may be useful to identify high risk group of patients who can
benefit from low dose CT for early detection of lung cancer. Recently, the main driver
oncogenic pathways for lung adenocarcinoma had been well characterized which
revealed distinct difference between East and West populations. We developed a
strategy for individualized therapy of lung cancer patients based on detection of genetic
alterations to predict the response to target therapy; including the EGFR (50%,
response to Gefitnib, Erlotinib, Afatinib), EML4-ALK(3-5%, Crizotinib), KRAS(5%,
Sorafenib, chemotherapy), MET(3-5%, ARQ-197, others), BRAF(3%, Sorafenib, others),
ERBB2(3%, Afatinib or Trastuzumab), and others. The lung cancer study group
established lung adenocarcinoma cell lines with various EGFR sensitive and resistant
mutations and used them as model to screen for new leads that can overcome
EGFR-TKI resistance. They also identified gene expression and microRNA signatures
and pathways that are associated with lung cancer progression metastasis. The
biomarkers may assist to stratify the risk and identify druggable targets for
personalized therapy of lung cancer patients.