ELCC News: A new genetic signature helps identify risk of relapse in patients with completely resected early NSCLC

The majority of the genes in the classifier are either immune-derived or immunomodulatory

A new genetic signature identified by Spanish researchers may provide robust and objective information about which patients with completely resected early stage non-small cell lung cancer (NSCLC) are at low or high risk of relapse following surgery, investigators report at the 3rd European Lung Cancer Conference (ELCC) in Geneva, Switzerland (18-21 April, 2012). Their work could also open new avenues for immunotherapy for lung cancer.

Researchers hope that identifying which patients have the greatest risk of relapse will allow focusing on other treatment strategies. A multidisciplinary team of researchers from Hospital Clinico San Carlos, Madrid, have found a 50-gene predictor that appears to be capable of doing just that. In a study of 84 patients with stage I and II NSCLC, who had undergone surgery to remove their tumour, the gene signature accurately predicted which patients were at low risk of relapse.

An ‘immune’ signature shows that patients with low risk of relapse have an enhanced immune response against the tumour

The researchers extracted RNA from frozen samples with more than 70% tumour cells. Tumours were analysed using microarray expression. The data were normalised and subjected to unsupervised analysis to classify samples based on expression profiles. Association of identified molecular subgroups with clinical, pathological and molecular variables and disease-free survival was analysed.

Following patients for six years, the researchers were able to correlate gene expression patterns with the clinical course of the disease, as well as the risk of relapse. At the meeting they reported that the genes of the predictor were overexpressed in roughly one-third of the patients, all of whom had a low risk of relapse. Further analysis showed that these genes were related to the activity of B lymphocytes.

According to Dr Florentino Hernando, who presented the results at the meeting, the B cell-mediated immune response seems to have a very important role. The genetic profile identified by the researchers suggests that low-risk patients have an enhanced immune response against the tumour. Thus, treatments that may interfere with this response, such as post-surgical chemotherapy, must be reconsidered for the low-risk subgroup.

One-third of the patients show an overexpression of an ‘immune’ genetic signature in their tumour specimens that was associated with better prognosis. The fact that this B cell-dependent immune response was associated to the good outcome suggests researchers should investigate its therapeutic applications in the management of these patients after surgical resection.

A pressing need for defining patients at high risk of relapse for adjuvant studies

Commenting on the study, which he was not involved in, Prof David Carbone from the Vanderbilt-Ingram Cancer Center, said that the Spanish group studied tumours from patients with completely resected stage I and II NSCLC for gene RNA expression profiles using 41,000 different probes. Since over half of these patients relapse and die from their cancer in spite of complete resection, there is a pressing need for both defining those patients at the greatest risk of relapse for trials of adjuvant therapy, but also potentially avoiding the toxicity of adjuvant therapy in patients with a low risk of relapse. This is a potentially extremely important classifier, which if independently validated, could be the basis of such a test. It is interesting that the majority of the genes in the classifier are either immune-derived or immunomodulatory, suggesting a potential molecular basis for this observation. According to Dr Carbone, it would be interesting to compare the results of this classifier to simple quantitation of lymphocytic infiltration into the resected tumours. 
ELCC is organised by top experts in lung cancer and thoracic malignancies from ESMO and IASLC.

Abstract 250O
Prevention, Early detection, Prognosis, Epidemiology, Tobacco control
Proffered Paper session: Thursday, 19 April, 16:20-17:50, Room C