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Role of ctDNA in NSCLC

Insights From: Bruce E. Johnson, MD, Dana-Farber Cancer Institute
Published: Friday, Nov 08, 2019



Transcript: 

Bruce E. Johnson, MD:
One can follow circulating free DNA during the patient’s course. And particularly when you pick up the initial mutations, you can find not only the original BRAF mutation, but also there are co-mutations. You typically find mutations of [T]P53, or sometimes KRAS, and sometimes other ones at the time of diagnosis. So you can pick up the ones that you would also typically see in the tumor.

The part that’s pretty consistent is that if you have an effective drug or a combination of drugs that cause a clinical response, you’ll see a drop in the BRAF-mutant alleles. The percentage you can detect will go down if the patient is responding well. This has been seen with the oncogenic drivers. With EGFR mutants and ALK-rearranged tumors, you’ll see that mutated gene go down.

The other thing that can happen is you can see it start coming back up, typically after a period of 6 months to a year. It also corresponds when the tumors, as we assess them by CT [computed tomography] scans, begin to grow. As a matter of fact, sometimes you may see the mutant allele start to appear before you see evidence of radiographic progression. This is a sign that the tumor is becoming resistant.

Characterizing the circulating free DNA can help identify those genomic changes that cause resistance. If you get a mechanism, another mechanism evading the MAP kinase pathway, you can end up developing resistance. For instance, if you get an activating mutation of PI3 kinase, it can end up causing resistance. It can also get a mutation of 1 of the RAS family of genes: KRAS, HRAS, or NRAS.

The part that becomes somewhat of a challenge is some of the mechanisms of resistance activate a pathway without a genomic change. For instance, they could upregulate 1 of the proteins. Say, for instance, that they upregulate the epidermal growth factor receptor protein without a mutation. Within the tumor, you could detect by testing the tumor, but it’s difficult, or almost impossible, to see by measuring circulating free DNA. That number of the different mechanisms of resistance are not a secondary mutation but activation of a pathway without a genomic change.

The work at ESMO [European Society for Medical Oncology Congress] looked at 78 patients with BRAF-mutant non–small cell lung cancer who were treated with agents directed against BRAF and MEK. They followed the plasma. They showed a decline in the BRAF alleles with the treatment in most of the patients. And then with the emergence of resistance, they could pick up additional mutations that could activate the MAP kinase pathway, including a PI3-kinase mutation, a KRAS mutation. They were able to discover some but certainly not all the mechanisms of resistance by studying the circulating free DNA.


Transcript Edited for Clarity 
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Transcript: 

Bruce E. Johnson, MD:
One can follow circulating free DNA during the patient’s course. And particularly when you pick up the initial mutations, you can find not only the original BRAF mutation, but also there are co-mutations. You typically find mutations of [T]P53, or sometimes KRAS, and sometimes other ones at the time of diagnosis. So you can pick up the ones that you would also typically see in the tumor.

The part that’s pretty consistent is that if you have an effective drug or a combination of drugs that cause a clinical response, you’ll see a drop in the BRAF-mutant alleles. The percentage you can detect will go down if the patient is responding well. This has been seen with the oncogenic drivers. With EGFR mutants and ALK-rearranged tumors, you’ll see that mutated gene go down.

The other thing that can happen is you can see it start coming back up, typically after a period of 6 months to a year. It also corresponds when the tumors, as we assess them by CT [computed tomography] scans, begin to grow. As a matter of fact, sometimes you may see the mutant allele start to appear before you see evidence of radiographic progression. This is a sign that the tumor is becoming resistant.

Characterizing the circulating free DNA can help identify those genomic changes that cause resistance. If you get a mechanism, another mechanism evading the MAP kinase pathway, you can end up developing resistance. For instance, if you get an activating mutation of PI3 kinase, it can end up causing resistance. It can also get a mutation of 1 of the RAS family of genes: KRAS, HRAS, or NRAS.

The part that becomes somewhat of a challenge is some of the mechanisms of resistance activate a pathway without a genomic change. For instance, they could upregulate 1 of the proteins. Say, for instance, that they upregulate the epidermal growth factor receptor protein without a mutation. Within the tumor, you could detect by testing the tumor, but it’s difficult, or almost impossible, to see by measuring circulating free DNA. That number of the different mechanisms of resistance are not a secondary mutation but activation of a pathway without a genomic change.

The work at ESMO [European Society for Medical Oncology Congress] looked at 78 patients with BRAF-mutant non–small cell lung cancer who were treated with agents directed against BRAF and MEK. They followed the plasma. They showed a decline in the BRAF alleles with the treatment in most of the patients. And then with the emergence of resistance, they could pick up additional mutations that could activate the MAP kinase pathway, including a PI3-kinase mutation, a KRAS mutation. They were able to discover some but certainly not all the mechanisms of resistance by studying the circulating free DNA.


Transcript Edited for Clarity 
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