Genotyping in Lung Cancer: New Opportunities, New Challenges
Genotyping in Lung Cancer: New Opportunities, New Challenges
This is Mark Kris, from Memorial Sloan Kettering Cancer Center. Our current approach to treating people with lung cancer is to do up-front genotyping to find genetic aberrations that can lead to specific therapies or can be used to direct patients to clinical trials of agents specifically targeting those aberrations.
This is a rapidly evolving field. Already, the National Comprehensive Cancer Network (NCCN) guidelines recommend testing for multiple aberrations, and particularly for mutations in epidermal growth factor receptor (EGFR) and rearrangements in the anaplastic lymphoma kinase (ALK) gene.
We do molecular testing in all adenocarcinomas; large-cell carcinomas; and even in squamous carcinomas, particularly in never-smokers and patients who have tiny biopsy specimens, because some of those specimens could actually be adenocarcinomas or have adenocarcinoma components, and it is worthwhile doing this testing.
There are many different vendors of and platforms for molecular testing. Memorial Sloan Kettering, for example, has developed its own multiplex testing, called MSK-IMPACT, which tests for 341 genes that are found in a variety of cancers. Whatever platform you use, it is important to test for all actionable aberrations.
Genotyping is not simply a test. It requires interpretation by an experienced molecular pathologist, and the results are more like pathology reports than blood test results.
It is also important to determine the differences between normal and tumoral DNA. Some of the tests have a pool specimen of normal DNA. Other tests compare the patient specimen with the tumor specimen, which I find the most attractive, because it eliminates any mutations that are not found only in the tumor. There can be germline aberrations -- single-nucleotide polymorphisms, for example -- that can look like mutations in a tumor but in truth are not actionable.
When you look at these reports for an aberration, make sure that you know that it is clearly found in the tumoral DNA, and make your decisions on that basis.
A second topic of importance is the change in our approach. Although these tests typically can be done in a laboratory within a short period (between 1 and 5 days), the critical time factors are obtaining adequate tumor specimens, processing the specimens, and transporting specimens from one lab to another within an institution or from one institution to another. From a practical standpoint, this can take anywhere from 2 to 4 weeks, and it has become a huge issue in the care of people with lung cancer. Do you wait for these results or not? A big decision that none of us had to face a few years ago is trying to decide, along with the patient, whether or not to wait.
Clearly, it depends on the degree of symptoms that a patient is having, and you must assess the patient's comfort level. The use of a cell-cycle-targeted or DNA-targeted chemotherapy is always a good decision, whether the patient has an aberration or not. The data in patients who have a targetable genetic aberration, EGFR or ALK, show that many of our chemotherapy agents have better outcomes in the presence of a targetable mutation.
In the randomized trial comparing chemotherapy with gefitinib, the response rate in mutated patients to carboplatin and paclitaxel -- perhaps not the best regimen we have today -- was double that in patients without a mutation, with a response rate of nearly 50%. Although not quite as good as what we would hope to see with the targeted therapy, we would be very happy to offer a regimen with a 50% response rate.
When you do not have the information available and you feel that you need to proceed with a patient's treatment, the default is to give available cytotoxic chemotherapy or DNA-targeted chemotherapy. When the molecular testing results become available, you must decide whether to continue this chemotherapy or to change to a target therapy, if a target is identified. In those situations, unless there has been a severe degree of toxicity, I strongly urge you to continue the chemotherapy long enough to know whether the patient has benefited. Even if you choose not to continue that chemotherapy after receiving the genetic test results, at least you know whether those drugs are effective, so they can be recommended to the patient in the future. Today, virtually every patient who receives a targeted therapy suffers relapse at some point and has to receive chemotherapy.
New technologies and new capabilities have greatly helped the care of our patients. They have also given us new responsibilities and new challenges, and we are going to continue to grow and learn about how best to manage patients with and without genetic aberrations on our next-generation panels.
This is Mark Kris, from Memorial Sloan Kettering Cancer Center. Our current approach to treating people with lung cancer is to do up-front genotyping to find genetic aberrations that can lead to specific therapies or can be used to direct patients to clinical trials of agents specifically targeting those aberrations.
This is a rapidly evolving field. Already, the National Comprehensive Cancer Network (NCCN) guidelines recommend testing for multiple aberrations, and particularly for mutations in epidermal growth factor receptor (EGFR) and rearrangements in the anaplastic lymphoma kinase (ALK) gene.
We do molecular testing in all adenocarcinomas; large-cell carcinomas; and even in squamous carcinomas, particularly in never-smokers and patients who have tiny biopsy specimens, because some of those specimens could actually be adenocarcinomas or have adenocarcinoma components, and it is worthwhile doing this testing.
There are many different vendors of and platforms for molecular testing. Memorial Sloan Kettering, for example, has developed its own multiplex testing, called MSK-IMPACT, which tests for 341 genes that are found in a variety of cancers. Whatever platform you use, it is important to test for all actionable aberrations.
Interpreting Genotyping Test Results
Genotyping is not simply a test. It requires interpretation by an experienced molecular pathologist, and the results are more like pathology reports than blood test results.
It is also important to determine the differences between normal and tumoral DNA. Some of the tests have a pool specimen of normal DNA. Other tests compare the patient specimen with the tumor specimen, which I find the most attractive, because it eliminates any mutations that are not found only in the tumor. There can be germline aberrations -- single-nucleotide polymorphisms, for example -- that can look like mutations in a tumor but in truth are not actionable.
When you look at these reports for an aberration, make sure that you know that it is clearly found in the tumoral DNA, and make your decisions on that basis.
Whether to Wait or Not
A second topic of importance is the change in our approach. Although these tests typically can be done in a laboratory within a short period (between 1 and 5 days), the critical time factors are obtaining adequate tumor specimens, processing the specimens, and transporting specimens from one lab to another within an institution or from one institution to another. From a practical standpoint, this can take anywhere from 2 to 4 weeks, and it has become a huge issue in the care of people with lung cancer. Do you wait for these results or not? A big decision that none of us had to face a few years ago is trying to decide, along with the patient, whether or not to wait.
Clearly, it depends on the degree of symptoms that a patient is having, and you must assess the patient's comfort level. The use of a cell-cycle-targeted or DNA-targeted chemotherapy is always a good decision, whether the patient has an aberration or not. The data in patients who have a targetable genetic aberration, EGFR or ALK, show that many of our chemotherapy agents have better outcomes in the presence of a targetable mutation.
In the randomized trial comparing chemotherapy with gefitinib, the response rate in mutated patients to carboplatin and paclitaxel -- perhaps not the best regimen we have today -- was double that in patients without a mutation, with a response rate of nearly 50%. Although not quite as good as what we would hope to see with the targeted therapy, we would be very happy to offer a regimen with a 50% response rate.
When you do not have the information available and you feel that you need to proceed with a patient's treatment, the default is to give available cytotoxic chemotherapy or DNA-targeted chemotherapy. When the molecular testing results become available, you must decide whether to continue this chemotherapy or to change to a target therapy, if a target is identified. In those situations, unless there has been a severe degree of toxicity, I strongly urge you to continue the chemotherapy long enough to know whether the patient has benefited. Even if you choose not to continue that chemotherapy after receiving the genetic test results, at least you know whether those drugs are effective, so they can be recommended to the patient in the future. Today, virtually every patient who receives a targeted therapy suffers relapse at some point and has to receive chemotherapy.
New technologies and new capabilities have greatly helped the care of our patients. They have also given us new responsibilities and new challenges, and we are going to continue to grow and learn about how best to manage patients with and without genetic aberrations on our next-generation panels.
