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Malignancy-risk gene signature developed for early-stage NSCLC
Chen DT. J Natl Cancer Inst. 2011;103:1859-1870.
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A malignancy-risk gene signature originally developed for breast cancer has predictive and prognostic value for patients with early-stage non–small cell lung cancer, according to study results published in the Journal of the National Cancer Institute.
Examining a malignancy-risk gene signature derived from a comparison of normal and malignant breast tissues, Dung-Tsa Chen, PhD, and colleagues from the Moffitt Cancer Center in Tampa, Fla., determined that the signature included genes involved in proliferation (56 of the 94 malignancy-risk genes, 59.6%) and with the loss of cell cycle control in the earliest stages of general tumor development.
To test the application of a malignancy-risk gene signature on other cancer types, researchers analyzed data from the Director’s Challenge Consortium for the Molecular Classification of Lung Adenocarcinoma, a large retrospective, multisite microarray study for lung adenocarcinomas. Four hundred forty-two samples were included for statistical analysis, with OS as the primary outcome variable and a median follow-up of 3.92 years — 255 samples were from living patients and 187 samples were from those who had died.
In addition, two independent NSCLC microarray datasets and one breast cancer dataset were included to corroborate the malignancy-risk gene signature: GSE13213 (with 117 lung adenocarcinomas samples), GSE14814 (randomized controlled trial of patients who received adjuvant chemotherapy vs. observation alone) and GSE10780 (dataset of 143 normal breast and 42 tumor samples).
“To the best of our knowledge, our study is the first to show a high consistency of the gene signature on both breast cancer and NSCLC,” Chen said in a press release. “The gene signature demonstrated a statistically significant association with overall survival and other clinical predictors in NSCLC.”
According to the analysis results, the malignancy-risk gene signature was associated with OS (P< .001) of NSCLC patients, and further corroboration with the two independent datasets demonstrated that the malignancy-risk score had considerable predictive value. Among patients who did not receive adjuvant chemotherapy, those with a low malignancy-risk score had increased OS compared with a high malignancy-risk score (P=.007 for GSE13212 and P=.01 for the GSE14814), demonstrating a prognostic value. Also, in the GSE14814 dataset, patients receiving adjuvant chemotherapy survived longer in the high malignancy-risk score group (P=.03) and were observed to have a statistically significant interaction between adjuvant chemotherapy and the signature (P=.02).
“Additionally, the malignancy-risk gene signature has demonstrated the potential to identify early-stage NSCLC patients who would be likely to benefit from adjuvant chemotherapy,” Chen said. “This malignancy-risk gene signature may provide an additional tool to help identify a subset of patients at high-risk for low overall survival and who may benefit from [adjuvant chemotherapy].”
Disclosure: The researchers report funding support from NIH, US Army Medical Research and Materiel Command, National Functional Genomics Center project and the Taiwan National Science Council.
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The article published by Dr. Dung-Tsa Chen and colleagues utilized the malignancy-risk gene signature derived from previous breast tissues studies, and applied now to analyze the microarray data from the 442 NSCLC patients in the Director's Challenge Consortium. The gene signature was found associated with overall survival and was a prognostic and predictive indicator in early-stage NSCLC, validated by two independent datasets. This is another good step forward in pursuing genomics signature, beyond histologic staging, to select early-stage resected NSCLC most beneficial for adjuvant chemotherapy, which would have high clinical use impact.
Another earlier report from Dr. Ming-Sound Tsao and colleagues (J Clin Oncol 2010;28:4417-4424) on the identification of 15-gene expression signature as the first such prognostic signature represents a perseverant effort in this research direction. Ultimately, validation studies in larger independent datasets, and prospective clinical trial studies would be needed for changing practice. The bar is not low indeed. Despite ongoing debates on the expected standards of genomics prognostic signature studies for clinical use (Subramanian J & Simon R, JNCI 2010;102: 464-474; Nat Rev Clin Oncol 2010;7:327-334; Boutros PC et al. JNCI (correspondence) 2010; 102:1677-1678), for now, I suspect the debate and the quest would both continue on … for a good common cause.
Patrick C. Ma, MD, MS
Director of Aerodigestive
Oncology Translational Research
Taussig Cancer Institute
The Cleveland
Clinic
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