Novel test identifies patients most likely to benefit from ALK inhibition therapy
Approximately one in 20 patients with non-small cell lung carcinoma (NSCLC) has chromosomal aberrations targeting the anaplastic lymphoma kinase (ALK) gene. This has considerable implications for treatment because these patients are highly responsive to ALK-specific kinase inhibitors such as crizotinib. However, current diagnostic tests have limitations. Researchers have now developed and tested a promising new method for screening ALK fusions in NSCLC. This new diagnostic assay offers a cost-effective and easy-to-perform alternative to existing tests. The study is published in The Journal of Molecular Diagnostics.
Crizotinib is a protein tyrosine kinase inhibitor approved by the FDA for the treatment of locally advanced or metastatic ALK-positive NSCLC as detected by an FDA-approved test and is undergoing phase III clinical trials. It is crucial to the clinical success of ALK inhibitors to identify those patients most likely to benefit from ALK inhibition. The latest National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology now recommend upfront ALK screening for all patients with NSCLC.
There are several clinically validated methodologies currently available for the detection of ALK fusions, including fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), and reverse transcription-polymerase chain reaction (RT-PCR). Crizotinib-centered clinical trials currently utilize a FISH-based test that was recently approved by FDA as the standard companion diagnostic test for crizotinib. However, it is complex and has considerable limitations in terms of cost and throughput, making it difficult to screen large numbers of patients.
"The FISH assay has undergone extensive validation in clinical setting and is currently the gold standard for ALK fusion detection," say lead investigators Dong-Wan Kim, MD, PhD, Seoul National University Hospital, Seoul, South Korea, and Mao Mao, MD, PhD, Pfizer Oncology, California. "A disadvantage of this diagnostic assay, however, lies in the fact that the signal can be subtle and consequently hard to interpret, requiring specialized technical expertise. It is also considerably more expensive compared with IHC and RT-PCR."
In the early phase trial of crizotinib, approximately 1500 patients were screened by FISH to identify 82 ALK-positive patients. The large number of patients qualifying for screening underscores the need for a high throughput and cost- effective screening modality. "An optimal assay should therefore not only be sensitive and specific, but also be economical, easy to perform, preferably automated, and readily adaptable to workflows of clinical service laboratories," continue the investigators.
To explore alternative screening modalities for detecting ALK fusions, they designed a novel method for detecting ALK fusions by direct, multiplexed transcript profiling using the gene expression platform from NanoString. They tested their assay in 66 archival NSCLC samples which had been independently tested by both FISH and IHC methods in terms of sensitivity, specificity, reproducibility, and concordance to prior FISH and IHC.
The results were highly concordant to previous results obtained by FISH and IHC and the investigators were able to successfully detect low-level ALK fusion transcripts in samples with low tumor cell content. All samples predicted to be positive in the assay responded favorably to crizotinib.
"While further testing on a larger sample size is needed for this assay to be considered in clinical practice, we have demonstrated that it offers a cost-effective, easy to perform, high-throughput, and FFPE-compatible screening alternative for detecting ALK fusions," conclude the investigators.
More information: "Multiplexed Gene Expression and Fusion Transcript Analysis to Detect ALK Fusions in Lung Cancer," Maruja E. Lira, Tae Min Kim, Donghui Huang, Shibing Deng, Youngil Koh, Bogun Jang, Heounjeong Go, Se-Hoon Lee, Doo Hyun Chung, Woo Ho Kim, Eric F.P.M. Schoenmakers, Yoon-La Choi, Keunchil Park, Jin Seok Ahn, Jong-Mu Sun, Myung-Ju Ahn, Dong-Wan Kim, and Mao Mao. DOI: dx.doi.org/10.1016… .2012.08.006. The Journal of Molecular Diagnostics, Volume 15, Issue 1 (January 2013)
Journal reference: Journal of Molecular Diagnostics
Provided by Elsevier
- Study: Inexpensive method detects ALK rearrangement in lung cancer patients Aug 02, 2011 | not rated yet | 0
- Not all lung cancer patients who could benefit from crizotinib are identified by FDA-approved test Aug 28, 2012 | not rated yet | 0
- Phase III trial shows crizotinib superior to single-agent chemotherapy for ALK-positive lung cancer Sep 30, 2012 | not rated yet | 0
- Study examines drug resistance in ALK positive lung cancer Jan 19, 2012 | not rated yet | 0
- First and only therapeutic drug for ALK-positive lung cancer approved Aug 31, 2011 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
Why is zone 1 in liver more prone to ischemic injury?
May 23, 2013 Hi, Is it because around central vein, there is only deoxygenated blood from the vein where as in the periphery there is hepatic artery. Also why...
How can there be villous adenoma in colon, if there are no villi there
May 22, 2013 As title suggest. Thanks :smile:
How can there be a term called "intestinal metaplasia" of stomach
May 21, 2013 Hello everyone, Ok Stomach's normal epithelium is simple columnar, now in intestinal type of adenocarcinoma of stomach it undergoes "intestinal...
Pressure-volume curve: Elastic Recoil Pressure don't make sense
May 18, 2013 From pressure-volume curve of the lung and chest wall (attached photo), I don't understand why would the elastic recoil pressure of the lung is...
If you became brain-dead, would you want them to pull the plug?
May 17, 2013 I'd want the rest of me to stay alive. Sure it's a lousy way to live but it beats being all-the-way dead. Maybe if I make it 20 years they'll...
MRI bill question
May 15, 2013 Dear PFers, The hospital gave us a $12k bill for one MRI (head with contrast). The people I talked to at the hospital tell me that they do not...
- More from Physics Forums - Medical Sciences
More news stories
By discovering the new mechanism by which estrogen suppresses lipid synthesis in the liver, UC Irvine endocrinologists have revealed a potential new approach toward treating certain liver diseases.
Medical research May 23, 2013 | not rated yet | 0 |
Aortic arch pulse wave velocity, a measure of arterial stiffness, is a strong independent predictor of disease of the vessels that supply blood to the brain, according to a new study published in the June issue the journal ...
Medical research May 23, 2013 | not rated yet | 0
Since the discovery of Prontosil in 1932, sulfonamide antibiotics have been used to combat a wide spectrum of bacterial infections, from acne to chlamydia and pneumonia. However, their side effects can include serious neurological ...
Medical research May 23, 2013 | not rated yet | 0 |
Scientists at the National Institutes of Health report they have discovered in mouse studies that a small molecule released in the spinal cord triggers a process that is later experienced in the brain as ...
Medical research May 23, 2013 | 5 / 5 (3) | 0 |
Spanish researchers have discovered that the daily clearance of neutrophils from the body stimulates the release of hematopoietic stem cells from the bone marrow into the bloodstream, according to a report published today ...
Medical research May 23, 2013 | 5 / 5 (2) | 0
Two mutations central to the development of infantile myofibromatosis (IM)—a disorder characterized by multiple tumors involving the skin, bone, and soft tissue—may provide new therapeutic targets, according to researchers ...
4 hours ago | 5 / 5 (1) | 0 |
(Medical Xpress)—A new study by researchers in the US has shown that an ancient virus can be modified to help in the fight against the simian immunodeficiency virus SIV, which is the equivalent in monkeys ...
9 hours ago | 5 / 5 (3) | 0 |
Talking on a hands-free device while behind the wheel can lead to a sharp increase in errors that could imperil other drivers on the road, according to new research from the University of Alberta.
3 hours ago | not rated yet | 0
Women at a particular stage in their monthly menstrual cycle may be more vulnerable to some of the psychological side-effects associated with stressful experiences, according to a study from UCL.
6 hours ago | 5 / 5 (1) | 0 |
Biological processes are generally based on events at the molecular and cellular level. To understand what happens in the course of infections, diseases or normal bodily functions, scientists would need to ...
7 hours ago | 5 / 5 (2) | 0 |
Kate O'Reilly's spring allergy survival kit includes the usual stuff - nasal sprays, allergy pills and a box of tissues. This season, she's added a new weapon to her line of defense: an app on her smartphone.
4 hours ago | not rated yet | 0