The investigation was conducted in individuals with non-small-cell lung cancer (NSCLC), although investigators are already using it in a variety of other cancers as well. The study is published in the cancer journal, Annals of Oncology this week.
Individuals who suffer with NSCLC could have mutations in any of at least 14 different genes, although the number could be even higher. So far, it has only been possible to look for single or a small number of genetic mutations, but as several genes are found to be involved in more cancers, it is vital for researchers to develop methods to determine the mutational status of numerous genes at once.
Assistant Professor of Medicine at Harvard Medical School and thoracic medical oncologist at the Massachusetts General Hospital Cancer Center (Boston, USA), Lecia Sequist (MD, MPH), and Dora Dias-Santagata (PhD), who is co-director of the Translational Research Laboratory in the Massachusetts General Hospital Pathology Department and Instructor of Pathology at Harvard Medical School, and their colleagues have created a clinical test (SNaPshot).
More than 50 well-known sites in 14 key cancer genes can be tested with SnaPshot, with just 2.8 weeks as the average time from a sample being sent for testing to receiving final results. KRAS, HER2, BRAF and EGRF are just some of the genes included.
The test amplifies multiple mutation sites in different genes by using a method called "multiplex PCR", in a single polymerase chain reaction (PCR) experiment, saving a significant amount of time and effort.
Dr. Dias-Santagata said:
"This test allows us to look for a defined set of common mutations that occur in cancer cells, but not in the other cells of the body. These mutations affect genes that disrupt the checks and balances that usually govern the behavior of normal cells, giving the mutant cells an advantage to divide and multiply, and the potential to give rise to a tumor. Targeted cancer therapies or "smart drugs", each developed to fight a specific group of genetic aberrations, are now available.
Because each tumor will harbor a specific set of mutations, the SNaPshot test allows us to match individual patients with the therapies that will most likely be effective in treating their cancer. Choosing the right therapy can raise response rates in NSCLC patients from around 20-30% to 60-75% and may improve survival."
From March 2009 to May 2010, researchers evaluated 589 samples taken from individuals with NSCLC using SNaPshot. Out of the samples taken 546 had sufficient tissue to be tested. Turnaround time varied from one to 8.9 weeks - the longer time usually resulted from samples being retested. In 51% (282) of the samples one or more mutations or rearrangements were discovered, with the most prevalent being in the EGRF (13%), ALK (5%) KRAS (24%) PIK3CA (4%) and TP53 (5%) genes.
170 out of the 353 participants with advanced disease (stage IIIb, IV or recurrent), had genetic mutations or rearrangements in ALK, BRAF, HER2, PIK3CA, EGRF and KRAS genes. These patients were classified as "potentially targetable" as they could join clinical trials analyzing medications targeting these genetic changes. A further 30 participants with EGRF mutations were treated with erlotinib (an EGRF inhibitor, already used to treat individuals with lung cancer) outside a clinical trial.
Prof. Sequist explained:
"To our knowledge we are the first center to offer this broad multiplexed genetic screening to all non-small-cell lung cancer patients. Broad genotyping is going to become part of everyday care for lung cancer patients - the field is clearly moving in this direction. Our study is exciting because it demonstrates that indeed it is possible today to integrate testing for multiple genetic biomarkers into a busy clinic and steer patients toward personalised therapies."
Dr. Dias-Santagata said:
"In contrast with prior genotyping strategies (mainly focused on testing EGFR and KRAS), employing a broad gene panel enabled us to provide a therapeutic alternative to lung cancer patients whose tumors harbored much less frequent genetic abnormalities (such as mutations in PIK3CA and BRAF, or rearrangements in ALK). Taken together, these individuals accounted for around ten percent of our patient population, but they would have remained 'invisible' in the absence of a comprehensive genotyping panel, like the one used here."
According to Sequist and Dias-Santagata, SNaPshot can be performed in the majority of existing clinical molecular diagnostic laboratories affiliated to hospitals and other institutions, using equipment already available.
Even though SNaPshot was primarily used on individuals with NSCLC, Dr Dias-Santagata and her team are currently using it in a variety of solid tumors, such as breast, gliomas and colorectal. They are also planning to extend their examination to cancers of the blood, including acute myeloid leukemia.
Dr. Dias-Santagata explained:
"While the present report describes the results of lung cancer genotyping, the SNaPshot test has been making a difference to clinical decision-making for a broader range of cancer patients. Future goals for testing involve the use of several technologies to obtain a more detailed genetic signature for each tumor. We hope that this approach will help us identify therapeutic options for a much larger fraction of cancer patients and provide a good resource to understand differences in response to therapy."