The accelerating pace of scientific discovery, profusion of genetic advances and explosion of big data has led to a sense that the cure for all disease is at hand. Every day we are offered the opportunity to explore our genetic heredity, measure our telomeres or perform a buccal smear (mouth swab) to predict our future response to drugs.
In cancer, this has been associated with the explosive growth of genomic analyses that analyze patient’s paraffin-fixed (wax embedded) tumor blocks in the hope of identifying targets for the newest classes of drugs that block mutations, amplifications and duplications.
We can imagine a future when patients will arrive at their doctor's office and instruct their physicians on exactly the drugs and doses that they should receive.
Despite the promise, the reality has been somewhat disappointing.
Medical oncologists are coming to realize that gene profiles usually provide more questions than answers. The impressive collection of mutational findings is generally not associated with actionable “targets”, effective drug choices or available clinical trials for patient accrual. So what’s a patient to do?
Looking at the Newest Targeted Drugs
Some years ago we reported our observations with the newest targeted agents. We were interested to see how drugs that inhibited specific cell pathways worked in different tumor types. As a backdrop, we already knew that some cancers responded very well to conventional chemotherapies.
Among them were small cell lung, leukemia, lymphoma and ovarian cancers. When we examined these chemo-responsive tumors we found, in some cases, that the tumors for which current chemotherapies worked very well were often less likely to respond to the newer classes of “targeted” agents.
Our observations suggested that there were really two types of cancer.
One group behaves like the model cell lines that were used for many years in drug development. These cancers tend to grow rapidly and often carry DNA-repair defects that make them responsive to conventional drugs.
The second group is those historically drug resistant tumors that we now understand carry unique drivers rendering them more responsive to the new “targeted” inhibitors.
Diagnosis - Stage 4 Stomach Cancer
This 53 year old gentleman presented with a rapidly growing gastric (stomach) cancer and transfusion-dependent bleeding. After undergoing a diagnostic endoscopy, confirming the mass in the stomach, he travelled to LA to seek opinions. He was offered chemotherapy by one qualified oncologist in LA and then requested a consultation with me shortly thereafter.
He was a healthy, vigorous and youthful gentleman who looked well despite his diagnosis of Stage 4 stomach cancer.
He was very familiar with our functional profiling assay technique (we call it EVA-PCD) that uses tissue analysis and requested a biopsy. At the patient and his family’s request we also submitted a portion of the biopsy specimen for genomic analysis. While we awaited the gene profile results, our EVA-PCD test was completed.
Although there are many treatment options for stomach cancer, this patient’s profile perfectly matched one drug combination known by the acronym FOLFOXIRI. In light of his advanced condition, we recommended that treatment begin immediately.
The patient required another blood transfusion before we could begin treatment and the first days of therapy were a bit rocky. But, by the second week, as cycle 2 began, he looked and felt much better. His pain had resolved and the evidence of stomach bleeding had ceased. When I inquired, he described himself as "10 out of 10."
Results of His Gene Profile
With Cycle 2 of FOLFOXIRI underway, the results of the gene profile arrived. They were disappointing, but not unexpected. The tumor carried no actionable mutations.
Although there were several interesting changes like a chromosome remodeling gene often found in uterine cancers or changes in a DNA-related-protein gene, sometimes seen in leukemia, absolutely nothing could be directly targeted with an available drug.
His Cancer Doesn't Fit the Fashionable Trend
With a 50% decline in tumor marker after a single cycle of therapy, this patient is a living, breathing example of exactly what we had observed years earlier.
He is one of the many patients whose cancers don’t fit the current trend in “targeted therapy”. These patient’s tumors proliferate rapidly or use DNA in ways that make them targets for conventional chemotherapy. After all, he carries no actionable mutations.
For him and patients like him the new era of targeted therapy left them behind. His tumor, it seems, only responds to what, in the current parlance, would be unfashionable drugs.
What Can We Learn?
There are many implications.
The first is that new drugs aren’t always better drugs.
The second is that patients must receive those drugs and combinations that work best for them, regardless of how in vogue those treatments may be.
The third is that cancer patients may represent distinct sub-groups. Older drugs, originally designed to stop cell proliferation may, in some patients, be just right. On the contrary, those tumors with specific drivers, that utilize nutrients differently, alter cell receptors or respond differently to survival signals may be quite resistant to classical cytotoxic drugs and can benefit from the newest agents.
Our job is to decide “who is who” before we treat them.
The take home message is that each patient must receive the right treatment for them the first time, every time.
Forcing patients to behave according to our current scientific dictates serves no one's purpose - not the patient, not the doctor, not the third party reimburser nor the pharmaceutical industry. Good medicine is good for everyone.
As always, I appreciate your thoughts and comments.