Since the origin of modern oncology in the 1950s, cancer patients have received chemotherapy drugs based on clinical trial results.
By failing to consider each drug’s mechanisms of action and factoring this into patient therapy selection, the majority of patients today receive drugs that are wrong for them. This results in toxicity (harm) but no benefit.
I was reminded of this dilemma by a recent lecture on the role of Doxorubicin (Adriamycin, also known as the “Red Death”) in breast cancer. Dr. Borges, a professor from the University of Colorado, provided a very thorough review of the literature on the role this potent chemotherapy drug has in breast cancer management.
Lacking the ability to select individual candidates for Adriamycin treatment, the medical oncology community has been forced to adopt a policy of giving everyone the drug and then waiting to find out what happened. Large clinical trials and meta-analyses, then parse the data and craft policies going forward.
This “Ready, Fire, Aim” approach to breast cancer medicine has exposed hundreds of thousands of women to a drug that carries risks of cardiac injury and leukemia but only has a limited impact on survival.
The EBCCTG 2023 report in The Lancet reviewed 100,000 patients and 86 clinical trials and found that: “Recurrence reductions were seen…leading to an absolute improvement of 2·6% in 10-year recurrence risk, and 1·6% in 10-year breast cancer mortality” (Lancet, 2023).
While a 1 to 2 % reduction in 10 year mortality is not zero, Dr. Borges opined that treatments should really be given more selectively, i.e. “give this chemotherapy only to those people who will benefit from it,” She said.
The obvious question is which patients will benefit from the drug?
On a molecular level we can examine genomic expression of this drug’s targets like the enzyme Topoisomerase II expression or amplification. But this is far from perfect and only applies to this one class of drugs.
We need to re-examine how and why all drugs work and then test our hypotheses in patient tissues before exposing patients to our best guesses. This is actually highly consistent with modern breast cancer management.
After all, today breast cancers that express Estrogen Receptors known as ER (+) receive estrogen-targeting hormonal therapy while those found ER (-) do not. That is, we measure the target (the estrogen receptor in the tissue) before we administer the treatment.
This incorporates each patient’s unique biology into drug selection. No one clamors over missed opportunities to treat ER (-) patients with hormones because these patients are statistically significantly less likely to respond.
We make a rational decision based upon data and experience to provide patients with better outcomes while saving time and money.
But the very same principles apply to all drugs. Chemotherapy drugs just like hormonal therapies are “right” for the “right” person based upon their mechanism of action.
In essence, chemotherapy plays upon a “response element” (a feature that makes the cell sensitive to that drug’s mechanism of injury) that may or may not be found in your tumor. If your cancer has an Adriamycin “response element” then your likelihood of benefit is better...Much better.
Adriamycin exposure causes injury that is either lethal or not lethal to a given patient’s breast cancer cells. When doxorubicin is lethal to the breast cancer cells, the patient has a better than two-fold higher likelihood of response. This means that the chemotherapy drug could be used only in those people for whom it is likely to work.
Everyone clamors for this capacity but refuses to use it.
Primary culture analyses recreate human tumor biology in a laboratory setting. If doctors were told that they could only administer Adriamycin with its the risk of cardiotoxicity, leukemia, gastrointestinal and cutaneous injury in patients who will benefit, they would make a bee-line for these laboratory services or lose the income and patient throughput that their practices depend upon.
Do we need to wait until another 100,000 patients are treated with Adriamycin before we decide how best to use this drug?
More to the point, do we need to wait until 100,000 patients are treated with Adagrasib, Alpelisib or Capaversitib, all highly selected targeted agents before we learn how to use these drugs?
Cancer patients do not have the time and increasingly do not have the patience to wait until the oncology community at its glacial pace identifies patients for treatment.
Cancer drugs work because they induce specific and selective injuries to cells. Only those cells sensitive to injury will respond and only those patients whose cells respond in the tissue culture studies are likely to benefit when treated.
We have wasted enough time on clinical trials to know cancer patients must be treated individually.
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