Determining Genetic Signature of Lung Tumours Can Help Guide Treatment

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Title: Determining Genetic Signature of Lung Tumours Can Help Guide Treatment
URL: http://www.pslgroup.com/dg/221B02.htm
Doctor's Guide
May 20, 2008

BOSTON -- May 20, 2008 -- The first US clinical trial using genetic screening to identify lung tumours that are likely to respond to targeted therapies now supports the use of those drugs as first-line treatment rather than after standard chemotherapy has failed.

"This is a pivotal clinical trial that demonstrates the power of personalised medicine in lung cancer treatment," says study leader Lecia Sequist, MD, MPH, Assistant Physician, Department of Medicine, Massachusetts General Hospital (MGH) Cancer Center, Boston, Massachusetts, and Instructor, Department of Medicine, Harvard Medical School, Cambridge, Massachusetts. "It is an exciting glimpse into what we hope is the future of cancer care. Instead of a 'one-size-fits-all' therapy, we are moving towards finding the best treatment for each patient."

Until recently, there were no treatment options for non-small-cell lung cancer (NSCLC) patients in whom chemotherapy failed. Gefitinib, which disables the epidermal growth factor receptor (EGFR) on the surface of lung cancer cells, was approved in 2003 for treatment of NSCLC. Although it only shrank tumours in less than 15% of patients, in those whom it did help, responses were rapid and dramatic.

In 2004 MGH Cancer Center researchers and a team from the Dana-Farber Cancer Institute (DFCI), Boston, Massachusetts, both discovered why gefitinib's success was confined to a limited group of patients. Specific EGFR mutations that were probably responsible for a tumour's development also made the cancer sensitive to gefitinib treatment. Subsequent to that announcement, the Laboratory for Molecular Medicine at the Harvard-Partners Center for Genetics and Genomics, Cambridge, Massachusetts, developed a test to screen for these sensitising mutations.

Late in 2004 a collaborative group led by MGH investigators began the current study, designed to see whether using gefitinib as an initial treatment for patients with a sensitising EGFR mutation would improve treatment results. Out of 98 NSCLC patients screened at 11 centres -- including the MGH Cancer Center and DFCI -- over a 2-year period, 34 patients had a sensitising mutation. Of those patients, 31 entered the trial and began receiving daily oral doses of gefitinib instead of standard chemotherapy. Gefitinib treatment continued indefinitely unless significant side effects occurred or tumour growth continued or resumed.

All but 2 of the participants responded positively to gefitinib treatment, with their tumours either shrinking significantly or not growing for a month or longer. At the end of the study period, 14 patients had died but 17 remained alive. The overall survival rate and the length of time until participants' tumours resumed growing were 2 or 3 times greater than would be expected with standard chemotherapy, Dr. Sequist explains. Only 1 participant dropped out because of treatment side effects.

The current study also analysed the specific EGFR mutations in participants' tumours to see if there were differences in the response to treatment. Patients with the 2 most typical mutations had vigorous responses to gefitinib, but the 7 patients found to have atypical mutations had a more limited response. None of the atypical cases had tumour shrinkage, but the majority had disease stabilisation for a period of time. Two patients who experienced rapid regrowth of their cancers were found to have additional EGFR mutations that previous research had indicated conferred resistance to the drug. It has been theorised that those resistance mutations develop in response to treatment, but this is the first observation of the mutations' being present before treatment began.

"It's starting to look like the strategy of genomically-directed cancer therapy will need to incorporate testing for multiple genotypes -- screening for 3, 4, or even more genetic markers -- some of which may indicate likelihood of response to treatment, and others the chance of resistance," says Dr. Sequist. "We think these results will also apply to other effective EGFR inhibitors, and we hope they can be duplicated for other types of cancer that involve these mutations. But what is needed next is a larger-scale, randomised clinical trial comparing an EGFR blocker with standard therapy in a genotype-selected population."

Source: Journal of Clinical Oncology

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