Genetic Determinants of Lung Cancer Survival

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant): Prognosis following a diagnosis of primary lung cancer is very poor: The one-year survival rate is only 20-50 percent for
advanced disease; the five-year survival rate ranges from 10-60 percent for
early stage to under 3 percent for late stage disease. It is vital that
survival be improved, because lung cancer will continue to be a significant
medical and public health burden for many decades even if all cigarette smokers
were to stop. Individualized prognostic predictors are needed. Recent basic
science studies suggest that genetic variations in human glutathione (GSH)
synthesis and GSH-dependent enzymes (GSH system) are promising candidates for
predicting platinum-based treatment outcomes and survival, but their
interaction with patient characteristics and disease features has not been
examined. Platinum compounds (cis- or carboplatin) are used in at least
two-thirds of late stage lung cancer patients. We propose to answer an
important question: whether patients' genotypes in the GSH system significantly
influence lung cancer survival over and above disease stage and treatment
modalities. Our primary goal is to test whether genotypes for four important
enzymes in the GSH system (gamma-GCS, GSTP1, GSTM1, and GSTT1) predict
short-term survival, which is defined as death due to lung cancer occurring
within three years of lung cancer diagnosis, among patients treated with
platinum compounds. Our secondary goal is to examine multiple risk factors
including, in addition to the genotypes stated above, cigarette smoking status,
clinical features of lung cancer (disease stage, tumor histology) and treatment
modality as modifiers for short-term survival.

We will enroll 800 primary lung cancer patients (with stage III and IV disease
and treated with platinum compound) and follow these patients for up to three
years after their diagnosis at the Mayo Clinic. Histologic subtypes under study
include adenocarcinoma, squamous cell, small cell and large cell carcinomas. At
least 500 deaths due to lung cancer are anticipated within three years of
diagnosis. Our analytic approach is hypothesis-driven, logically progresses
from descriptive statistics to survival analysis, and to multiple regression
models. From this pharmacogenetic-epidemiology study, we will confirm or refute
whether genotypes indicative of deficient or absent enzyme activities in the
OSH system predict better short-term survival and whether such a survival
benefit is only manifested among platinum-treated patients. Our results may
suggest a new direction to enhance lung cancer chemotherapy by suppressing or
depleting the relevant enzymes. Our results may also assist clinicians in
planning patient-specific therapy and more accurately predicting prognosis.
Through this project, we will establish a valuable data resource and an
infrastructure to study promising biological markers for short- and long-term
prognosis of lung cancer patients.
StatusFinished
Effective start/end date12/1/991/31/14

ASJC

  • Medicine(all)