Health News Review

The following is a guest blog post by one of our story reviewers, Harold DeMonaco of Massachusetts General Hospital (MGH), writing at my request about a paper in this week’s Annals of Oncology . He applies our ten criteria to what appears in the paper. (Disclosure: some of the authors of this paper work at the MGH, where DeMonaco is employed.)
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The promise of personalized medicine has been slow to come to fruition. The enthusiasm displayed a decade ago has been tempered by the difficulties in matching genetic mutations to specific diseases in individual patients. Much of the difficulty has been in the inefficient methods in identifying candidate mutations. The search for or identification of specific mutations that are associated with a disease is both time consuming and expensive.

Traditional treatments for non-small cell lung cancer (NSCLC) have not been particularly effective with response to standard chemotherapy in the 20-30% range with a time to recurrence of 3-5 months. In addition to not being particularly effective, traditional chemotherapy carries with it a host of side effects. The paradigm shifted with the development of targeted treatments that take advantage of the genetic differences seen between normal and cancer cell. The problem was identifying which patients had the particular genetic mutations that were associated with their disease. Although the knowledge in this area moves very quickly, the identification process has been tedious and expensive. If more than one mutation was involved, multiple testing was required.

So, a testing method that allows clinicians to search a multitude of candidate
gene mutations in a relatively short period of time, inexpensively and with good accuracy is a huge step in the right direction. The report from researchers published today in the Annals of Oncology describes their coordinated approach to gene mutation identification in patients with non-small cell lung cancer (NSCLC).

The technology used, called SNaPshot was developed by the investigators and is commercially available from Applied Biosystems and can simultaneously search for up to 50 multiple gene mutations at once. This approach has been applied in research involving diverse diseases including those in oncology, neurology and cardiology to name a few.

What the study is all about:

The investigators examined NSCLC pathology specimens prescreened for clinical reasons for a genetic mutation. After obtaining consent from the patients, the specimens were subjected to SNaPshot analysis. 546 samples were examined with one or more gene mutations seen in 282/546 (51%). Of the 353 patients enrolled with advanced disease (stage 3b, IV or recurrent), 170 had potentially targetable mutations (EGFR, KRAS, ALK, BRAF, PIK3CA and HER2). Of those, 64 enrolled in a clinical trial involving a targeted agent specific to their gene mutation. Thirty patients in this relatively small series had far less common mutations supporting the notion that broad based screening may be necessary.

The study also suggests that outcomes may be related to the specific genetic mutations identified but given the lack of full information on management, a detailed assessment could not be done so the results should be viewed as preliminary. Median overall survival in all 346 with advanced NSCLC was 21.7 months. Those with a particular mutation (KRAS) had a median survival of 16.4 months. Those with the EGFR mutation had a median survival of 34.3 months.

Importantly the results of the use of newly identified targeted therapies in this group of patients are not known. The real test of the approach will be its utilization in a large group of patients and will require assessment of the outcomes seen with either a group of patients treated based on existing technology or on the basis of a comparison to historical controls. This study was conducted in patients with non-small cell lung cancer and the results seen may or may not be applicable to other forms of cancer or other diseases.

In summary:

-The basic technology (SNaPshot) is commercially available and is in use for other purposes in most molecular diagnostics laboratories.

-The costs associated with the approach outlined are unknown but would likely be less than those seen if all of the genetic mutations were sought individually. Each of these tests costs thousands of dollars individually.

- The study is really an early proof of concept for the SNaPshot technology and its application for NSCLC. This study does NOT confirm that the approach will offer a meaningful improvement in patient outcomes in NSCLC or any other cancer or disease. The results suggest that this MAY offer a simpler and less costly way to identify the best treatment regimen for patients with NSCLC and potentially other forms of cancer where genetic mutations play a role. It also may offer a more rapid approach to identifying genetic mutations of interest in diseases where they have not been demonstrated to play a role.

-Since the test is diagnostic, it is unlikely that there are direct harms. However, tests that may be used to direct treatment have the potential to be wrong, subjecting patients to inadequate treatment regimens and potential treatment toxicity without adequate benefits.

-The SNaPshot technology has been around for a few years and is used currently by most molecular diagnostic labs. The application of a constructed multi-mutation panel for a specific disease is also not new having been used previously in cancer, neurology and cardiology. What is new is the specific use for NSCLC and the breadth of mutations targeted simultaneously.

-The authors of the paper appropriately provided a listing of all of the relevant potential for conflicts of interest. Several of the authors are the stated inventors of the SNaPshot genotying assay and are consultants for the company who brought it to market.

-Panels for identifying genetic mutations associated with disease have been known for some time and the data set is increasing daily.

Comments

Gregory D. Pawelski posted on November 10, 2011 at 11:01 am

This genotying assay is interesting because the realization is that genotype does not equal phenotype. The particular sequence of DNA that an organism possess (genotype) does not determine what bodily or behaviorial form (phenotype) the organism will finally display. Among other things, environmental influences can cause the suppression of some gene functions and the activation of others. The knowledge of genomic complexity tells us that genes and parts of genes interact with other genes, as do their protein products, and the whole system is constantly being affected by internal and external environmental factors.
The gene may not be central to the phenotype at all, or at least it shares the spotlight with other influences. Environmental tissue and cytoplasmic factors clearly dominate the phenotypic expression processes, which may in turn, be affected by a variety of unpredictable protein-interaction events. This view is not shared by molecular biologists, who disagree about the precise roles of genes and other factors, but it signals many scientists discomfort with a strictly deterministic view of the role of genes in an organism’s functioning.
Until such time as cancer patients are selected for therapies predicated upon their own unique biology, we will confront one targeted drug after another. A better solution to this problem is to investigate the targeting agents in each individual patient’s tissue culture, alone and in combination with other drugs, to gauge the likelihood that the targeting will favorably influence each patient’s outcome. Functionally profiling these results to date in patients with a multitude type of cancers suggest this to be a highly productive direction.