The premise that all cancers are driven by genetic mutations has led to the broad application of commercial services to report mutations. Cancer physicians and patients now often use genomic (DNA) tests as they seek answers to complex drug selection questions.
When these DNA changes are identified, patients are often treated with one of the new targeted agents designed to inhibit the pathway of interest (i.e. EGFR, ALK, Braf, etc.).
The belief that cancers are all driven by specific mutations has led to the frantic pursuit of “actionable” mutations. That is, changes that can be “drugged” by one the new targeted agents.
But for patients or physicians who have ever received one of these DNA reports they will know that many of the results are listed as “variants of uncertain significance” or VUS. This refers to gene changes that have not been established in the Cancer Genome Atlas to benefit from the newest targeted drugs. It doesn’t mean you won’t benefit, it means that the laboratory literally can’t say.
In a recent review, the percentage of mutations in the most common “actionable” genes that are reported as variants of uncertain significance (VUS) is enormous. For BRCA1, 75% are VUS. For BRCA2, it is 68%. In ATM, the incidence is 70%.
This leaves cancer patients and their physicians bewildered.
Is a variant of uncertain significance actionable? Could it represent a target for contemporary therapy? Would we administer a drug on the basis of these findings? All of these questions remain unanswered.
However, there is a way to answer these questions.
Genomic findings are a first step. They find targets. The question the patient wants to answer is “Can I hit the target?”
To answer this question, one must go several layers deeper from the DNA test to a measure of the actual tumor biology. This is the EVA/PCD™ platform that we apply to determine whether a targeted agent, when administered to a patient will actually work.
Every day in our laboratory we study over 170 small molecules that can actually tell patients whether their Variant of uncertain significance is significant for them.
Does this work? Yes, extremely well.
Our ABC news coverage of a gentleman from Des Moines, Iowa treated at the MD Anderson for a gastroesophageal junction (GEJ) adenocarcinoma is very instructive.
When his first line therapy failed, he left Texas to undergo a biopsy here at our hospital. The EVA/PCD™ identified significant activity for drugs that block a target known as EGFR. Puzzled by the findings, I requested the MD Anderson DNA analysis and right in the middle of the report was a variant of uncertain significance for EGFR.
His physicians dismissed the finding and did not recommend EGFR targeted therapy, but we absolutely knew from our EVA/PCD™ results that this variant of uncertain significance was very significant for him.
When he received the EGFR-based treatments guided by our EVA/PCD™ finding, he had a complete and durable remission, all after failing therapy at MD Anderson.
Genomic analyses provide information that can be useful, sometimes very useful. More often, however, it poses more questions than it answers.
What we need are results that can provide patients with truly actionable findings.
To do this, one must get layers deeper than gene profiles down to the level of human tumor biology. The EVA/PCD™ technology exists in our laboratory today.
The ex vivo analysis of programmed cell death EVA/PCD™ can distinguish variants of uncertain significance from actionable mutations. That is personalized medicine.
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