Originally published May 10.
At the European Lung Cancer Conference in Geneva last month several pharmacogenomics studies suggested future personalization of lung cancer treatments.
Among these studies was new subset analysis by Biodesix of a multi-center Phase III study that showed that the company's VeriStrat test was able to identify NSCLC patients most likely to have a "significant survival benefit" from treatment with Tarceva. VeriStrat, a mass spectrometry-based platform, analyzes patients' serum to determine if the patient is likely or not likely to benefit from Tarceva (PGx Reporter 05/05/10).
Other PGx studies presented at the conference focused on CXCR4 overexpression in non-small cell lung cancer and VEGF expression as it relates to response to anti-angiogenic drugs. Additionally, the International Association for the Study of Lung Cancer and the European Thoracic Oncology Platform's European EGFR Workshop Group proposed recommendations on EGFR mutation testing in NSCLC when patients are treated with AstraZeneca's Iressa. Below are the summaries of these three abstracts.
CXCR4 Overexpression by Immunohistochemistry Heralds Poor Outcome in Metastatic NSCLC
Shannon Otsuka and colleages from the Tom Baker Cancer Centre at the University of Calgary investigated the effect of CXCR4 expression on the progression of non-small cell lung cancer.
Between 2003 and 2006, the researchers gathered clinical and outcomes data on patients diagnosed with stage IV NSCLC at the Tom Baker Cancer. The researchers obtained formalin-fixed paraffin embedded tumor specimens from 303 patients diagnosed with stage IV NSCLC and generated 200 tissue arrays. Specimens were randomly assigned into tester and validator cohorts. CXCR4 expression within NSCLC cells was analyzed by immunohistochemistry using HistoRx's PM-2000 platform, which the researchers correlated with clinical outcome for 103 patients.
Although the overall survival of patients whose tumors were suitable for TA generation was similar to the general cohort, "high expressers" of CXCR4, representing 10.7 percent of the tested stage IV patients, "had a significantly poorer clinical outcome with a median overall survival of 2.7 months versus 6.1 months for the low expressers," the researchers reported. Additionally, researchers associated CXCR4 overexpression with squamous histology, smoking history, and a higher rate of brain metastases.
The researchers concluded that "CXCR4 is expressed in most NSCLC tumors," and that "CXCR4 overexpression is associated with significantly poorer survival in stage IV NSCLC patients." Furthermore, the study results suggest that new treatment strategies, as well as investigational anti-CXCR4 drugs, should be developed and tested in CXCR4 overexpressers. The team is currently validating this finding.
Molecular Expression of Angiogenic Markers in Early-Stage NSCLC: Evaluation of the Prognostic Role
Eloisa Jantus from the General University Hospital of Valencia and colleagues performed quantitative RT-qPCR analysis to gauge the expression of VEGF-A, -B, -C, -D, PlGF, and VEGFR-1, -2 and -3 in 135 frozen lung cancer specimens from untreated NSCLC patients who had undergone surgical resection. RNA was extracted using Invitrogen's Trizol reagent and RT-qPCR was performed using Life Technologies TaqMan probes.
The researchers correlated the expression of the angiogenic genes with clinico-pathological and survival variables, and found an overexpression of PlGF in tumors compared to normal tissues, with even higher expression in squamous cell carcinomas.
"There was no correlation between VEGF-A, VEGFR-1 and VEGFR-2 with the histology or tumor stage in our cohort," the researchers reported. However, "a strong positive correlation between the expression of VEGF-A and VEGFR-1 in tumor samples (p
"In NSCLC tumor samples, PlGF is overexpressed, especially in squamous cell carcinoma," the researchers concluded. "In addition, determination of VEGF-A and VEGFR-1 genes by RT-qPCR would be a useful clinical test to assess prognosis in NSCLC, due to the fact that higher levels of expression of both genes correlates with shorter overall survival."
This study was supported by a grant from the Instituto de Salud Carlos III in Madrid, Spain.
EGFR Mutation Testing in NSCLC: Clinical Recommendations From the European EGFR Workshop Group
The International Association for the Study of Lung Cancer and the European Thoracic Oncology Platform's European EGFR Workshop Group, which comprises biologists, pathologists, surgeons, chest physicians, and medical oncologists, developed recommendations to standardize EGFR mutation testing in NSCLC when patients are treated with the drug Iressa.
AstraZeneca's Iressa recently received marketing approval from European regulatory authorities for the treatment of patients with locally advanced or metastatic NSCLC, who have activating mutations of the EGFR-tyrosine kinase inhibitor. In the UK, AstraZeneca is currently paying for EGFR mutation testing for patients considering treatment with Iressa, under a patient access scheme with the National Health Service (PGx Reporter 04/07/10).
Although the American Society of Clinical Oncology's guidelines recommend EGFR mutation testing in NSCLC patients, "this procedure is less well established in European clinical practice," Robert Pirker from the Medical University of Vienna and colleagues said in their abstract. "These recommendations from a multidisciplinary European workshop will help to optimize routine EGFR mutation testing in Europe," they said.
After discussing all aspects of the EGFR mutation testing, such as biopsy, sampling, pathology, and mutation testing, Pirker et al. recommended that doctors should make the decision on when to order EGFR mutation testing for their NSCLC patients. They added that results from laboratories should be available within seven working days and recommended standardization of tumor sample handling.
"All patients with NSCLC may eventually be tested, but exceptions may be made when likelihood of mutation is low," said Pirker et al. They reached no consensus on pre-screening algorithms.
They recommended that in the ideal case, pathologists should report tumor histology and mutation status concurrently. In addition, sample size or quality, tumor nuclei percentage, methodology used, exons tested, and mutation present/absent should be included in the final report.
Many of the workshop's participants disclosed that they had consulted for or received payments from drug companies, including AstraZeneca, Merck, Eli Lilly, Boehringer Ingleheim, Roche, and others.